JP2008074875A - Sulfonamide for treating endothelin-mediated disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound for regulating the activity of an endothelin (ET) peptide, as the endothelium of blood vessels releases various materials acting on the blood vessels such as endothelin and the like which is a vasoconstrictive peptide originated from the endothelium, and a formulation for administering the compound to mammals. <P>SOLUTION: Thienyl-, furyl- and pyrrolyl-sulfonamides; pharmaceutically permissible salts of sulfonamides; formulations of the salts and the sulfonamides; and methods for modulating or altering the activity of the endothelin family of peptides using the formulations and sulfonamides are provided. In particular, formulations of sodium salts of N-(isooxazolyl)theinylsulfonamides, N-(isooxazolyl)furylsulfonamides and N-(isooxazolyl)pyrrolylsulfonamides are provided. A method for preparing an alkali metal salt of a hydrophobic sulfonamides is provided. The method includes a step for dissolving a free sulfonamide in an organic solvent in the presence of a saturated alkali metal salt solution and a step for recovering the formed sulfonamide salt from the organic solvent. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

RELATED APPLICATIONS This application is related to the US national phase and is a part of US Patent Application No. 08/934444 (Brief of SULFONAMIDES FOR TREATMENT OF ENDOTHELIN-MEDIATED DISORDERS) filed September 27, 1997 to Blok et al. This is a continuous continuation application The application is further a continuation-in-part of US patent application Ser. No. 08/847797 filed Apr. 28, 1997 to Blok et al. (Title of Invention “PROCESS OF PREPARING ALKALI METAL SALTS OF HYDROPHOBIC SULFONAMIDES”). With respect to the international phase, priority benefits are claimed for the above cited applications.

  This application is related to US patent application 08/934325 filed September 27, 1997 to Wu et al. (Invention name “SULFONAMIDS AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN”), and It is also related to the international patent application PCT / US97 / 17402 (name of invention “SULFONAMIDS AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN”) to Wu et al. Filed on Sep. 27, 1997. The application is related to US Patent Application No. 08/721183 to Chan et al. Filed Sep. 27, 1996 (Title of Invention “SULFONAMIDS AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN”); Is related to International Patent Application No. PCT / US96 / 04759 to Chang et al. Furthermore, US patent application 08/417075 to Chang et al., Filed April 4, 1995, which is now abandoned (invention name “THIENYL-, FURYL-, AND PYRROLYL SULFONAMIDES AND DERIVATIVES THEREOF THAT” MODULATE THE ACTIVITY OF ENDOTHELIN ”); and moreover, the US special feature for Chang et al. Filed on May 20, 1994. (Now U.S. Pat. No. 5,571,821) Application No. 08/247072 (entitled "SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN") in what can be described as related;

  Furthermore, US Patent Application No. 08/222287 to Chang et al. Filed on Apr. 5, 1994 (currently US Pat. No. 5,591,761) (invention name “THIOPHENYL-, FURYL- AND PYRROLYL-SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE” ACTIVITY OF ENDOTHELIN "); each of these applications is a U.S. Patent Application No. 08 / 142,552 (currently U.S. Pat. No. 5,514,691) to Chang et al. -(4-HALO-ISOXAZOLYL) -SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN "), US Patent Application No. 08/142159 to Chang et al. Filed Oct. 21, 1993 (currently US Pat. No. 5,464,853) (Invention) N- (5-ISOXAZOLYL) BIPHENYLSULFONAMIDES, N- (3-ISOXAZOLYL) BIPHENYLSULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN ) And US Patent Application No. 08 / 142,631 to Chang et al. Filed Oct. 21, 1993 (Title of Invention “N- (5-ISOXAZOLYL)-BENZENESULFONAMIDES, N- (3-ISOXAZOLYL) -BENZENESULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN ”).

  Where allowed, the subject matter of each of the above applications is hereby incorporated by reference in its entirety.

TECHNICAL FIELD The present invention relates to compounds that modulate the activity of endothelin peptides and formulations for administration of the compounds to mammals. In particular, preparations of sulfonamides as well as sulfonamide compounds (especially sodium salts of sulfonamide compounds) for administration for the treatment of endothelin-mediated disorders are provided. A process for the production of alkali metal salts of hydrophobic sulfonamides is also provided.

BACKGROUND OF THE INVENTION Vascular endothelium releases various vasoactive substances such as endothelin (ET), an endothelium-derived vasoconstrictive peptide (eg, Vanhoutte et al . (1986) Annual Rev. Physiol ., 48 : 307- ). 320; Furgotgott and Zawadski (1980) Nature 288 : 373-376). Endothelin (see Yanagisawa et al . (1988) Nature 332 : 411-415), first identified in the culture supernatant of porcine aortic endothelial cells, is a potent peptide vasoconstrictor with 21 amino acids. It is the most potent of the known vasoconstrictors and is produced by various cell types such as endothelium, trachea, kidney and brain cells. Endothelin is synthesized as a 203 amino acid precursor preproendothelin containing a signal sequence, which is cleaved by an endogenous protease to yield a 38 amino acid (human) or 39 (pig) peptide.

This intermediate, termed “large molecule endothelin”, is processed in vivo to a mature bioactive form by a putative endothelin converting enzyme (ECE) that appears to be a metal-dependent neutral protease (eg, Kashiwabara et al . (1989) FEBS Lttrs . 247 : 337-340). Cleavage is required to induce a physiological response (see, eg, von Geldern et al . (1991) Peptide Res. 4 : 32-35). In porcine aortic endothelial cells, 39 of the intermediate amino acid (large molecules endothelin) is hydrolyzed with ^Trp 21 -Val ²² bond, resulting in endothelin-1 and a C-terminal fragment. A similar cleavage occurs in human cells from a 38 amino acid intermediate. Three different endothelin isopeptides that exhibit potent vasoconstrictive activity, endothelin-1, endothelin-2 and endothelin-3 have been identified.

Three isopeptides, endothelin-1, endothelin-2 and endothelin-3 are encoded by three enzymes (Inoue et al . (1989) Proc. Natl, Acad. Sci. USA 86 : 2863- 2867; see also Saida et al . (1989) J. Biol . Chem ., 264: 14613-14616). The nucleotide sequences of the three human genes are highly conserved within the region encoding the mature 21 amino acid peptide, and the C-terminal portions of the peptides are identical. Endothelin-2 is (Trp ⁶ , Leu ⁷ ) endothelin-1, and endothelin-3 is (Thr ² , Phe ⁴ , Trp ⁵ , Tyr ⁶ , Lys ⁷ , Tyr ¹⁴ ) endothelin-1. Thus, these peptides are highly conserved at the C-terminus. Release of endothelins from cultured endothelial cells is regulated by various chemical and physical stimuli and appears to be regulated at the level of transcription and / or translation. Expression of the gene encoding endothelin-1 is increased by chemical stimuli such as adrenaline, thrombin and Ca ²⁺ ionophore. Endothelin production and release from the endothelium is stimulated by angiotensin II, vasopressin, endotoxin, cyclosporine and other factors (Brooks et al. (1991) Eur . J. Pharm ., 194 : 115-117), nitric oxide Is inhibited by.

Endothelial cells appear to secrete short-lived vascular endothelial cell-derived relaxing factor (EDRF) such as nitric oxide or related substances when stimulated by vasoactive agents such as acetylcholine and bradykinin (Palmer et al (1987) Nature , 327 : 524-526). Furthermore, endothelin-induced vasoconstriction is attenuated by atrial natriuretic peptide (ANP).

Endothelin peptides exhibit many physiological activities in vitro and in vivo . Endothelin induces strong and persistent vasoconstriction in vivo in rats and even in isolated vascular smooth muscle preparations. Endothelin further induces the release of eicosanoids and vascular endothelial cell-derived relaxing factor (EDRF) from the perfused vascular bed. Endothelin-1 intravenous administration and addition to blood vessels and other smooth muscle tissue produces long-lasting pressor effects and contractions, respectively (eg, Bolger et al . (1991) Can . J. Physiol . Pharmacol ., 69 : 406-413). For example, in isolated vascular sections, endothelin-1 is a potent (EC ₅₀ = 4 × 10 ⁻¹⁰ M), slow acting but long-lasting contractile agent. In vivo , a single dose increases blood pressure within about 20-30 minutes. Endothelin-induced vasoconstriction is not affected by antagonists to known neurotransmitters or hormonal factors, but is stopped by calcium channel antagonists. However, since long-lasting contractile responses to endothelin appear to require calcium influx, the effects of calcium channel antagonists are most likely due to inhibition of calcium influx.

Endothelin further mediates renin release, stimulates ANP release and induces positive inotropic effects in guinea pig atria. In the lung, endothelin-1 acts as a potent bronchoconstrictor (Maggi et al . (1989) Eur . J. Pharmacol ., 160 : 179-182). Endothelin increases renal vascular resistance, reduces renal blood flow, and reduces glomerular filtration rate. Endothelin is a potent mitogen for glomerular vascular membrane cells and induces a phosphoinoside cascade in such cells (Simonson et al. (1990), J. Clin . Invest . 85 : 790 -797).

The vascular system and other tissues such as intestine, heart, lung, kidney, spleen, adrenal gland and brain have specific high affinity binding sites for endothelin (dissociation constants in the range of 2-6 × 10 ⁻¹⁰ M). is there. Binding is not inhibited by catecholamines, vasoactive peptides, neurotoxins or calcium channel antagonists. Endothelin interacts with receptor sites distinct from other autonomic receptors and voltage-dependent calcium channels. Competitive binding studies indicate that there are multiple types of receptors with different affinities for endothelin isopeptides. Sarafotoxins, a group of peptide toxins from the venom of the snake Atractaspis eingardensis that causes severe coronary vasospasm in snake bite victims, have structural and functional homology with endothelin-1. , Competitively bind to the same pericardial receptor (Kloog et al . (1989) Trends Pharmacol . Sci. 10 : 212-214).

. ET termed _A and ET _B 2 different endothelin receptors have been identified, DNA clones encoding each receptor have been isolated (Arai et al (1990) Nature , 348: 730- 732; Sakurai et al . (1990) Nature , 348 : 732-735). According to the amino acid sequence of the protein encoded by the cloned DNA, each receptor has seven types of membrane spanning regions and appears to show structural similarity to G protein-binding membrane proteins. . Messenger RNAs encoding both receptors have been detected in various tissues such as heart, lung, kidney and brain. The distribution of receptor subtypes is tissue specific (Martin et al. (1989) Biochem . Biophys . Res . Commun ., 162 : 130-137). ET _A receptors appear to be selective for endothelin-1, which is prevalent in cardiovascular tissue. ET _B receptors are predominant in non-cardiovascular tissues such as the central nervous system and kidney, three endothelin isopeptide and interact (Sakurai et al (1990) Nature , 348:. 732-734) . Furthermore, ET _A receptors are located on vascular smooth muscle, and participate in vasoconstriction, cardiovascular diseases have been associated with kidney disease and central nervous disorders. On the other hand, ET _B receptors are located on the vascular endothelium is involved in vasodilation (Takayanagi et al (1991) FEBS Lttrs, 282:.. 103-106), it was associated with bronchoconstriction disorders.

Due to the distribution of receptor species and the differential affinity of each isopeptide for each receptor species, the activity of endothelin isopeptides differs in different tissues. For example, endothelin-1 inhibits ¹²⁵ I-labeled endothelin-1 binding in cardiovascular tissue, 40-700 times more potent than endothelin-3. Kidney, ^{125 I-labeled} endothelin-1 binding in non-cardiac tissues, such as adrenal and cerebellum, from being inhibited to the same extent by endothelin-1 and endothelin -3, ET _A receptors predominate in cardiovascular tissues , ET _B receptors are found to be prevalent in non-cardiovascular tissues.

In certain disease states, endothelin plasma levels are elevated (eg, International PCT application WO 94/27979 and US Pat. No. 5,382,569; the disclosures of which are hereby incorporated by reference in their entirety). Plasma levels of endothelin-1 in healthy individuals as measured by radioimmunoassay (RIA) are about 0.26-5 pg / mL. Endothelin-1 and its precursor macromolecular endothelin levels are elevated in shock, myocardial infarction, vasospasm angina, renal failure and various connective tissue disorders. Levels as high as 35 pg / mL have been observed in patients who have undergone hemodialysis or kidney transplantation or who suffer from cardiac shock, myocardial infarction or pulmonary hypertension (Stewart et al . (1991) Annals Internal Med ., 114 : 464-469). Since endothelin is thought to be a local rather than systemic regulator, endothelin levels at the endothelial / smooth muscle interface are likely to be significantly higher than circulating levels.

High levels of endothelin have also been measured in patients with ischemic heart disease (Yasuda et al . (1990) Amer . Heart . J. , 119 : 801-806; Ray et al . (1992) Br. Heart J. , 67 : 383-386). In patients with advanced atherosclerosis, circulation and tissue endothelin immunoreactivity are more than doubled (Lerman et al . (1991) New Engl . J. Med ., 325 : 997-1001). Endothelin immunoreactivity is increased in Buerger's disease (Kanno et al . (1990) J. Amer . Med . Assoc ., 264 : 2868) and Raynaud's disease (Zamora et al . (1990) Lancet, 336 : 1144-1147). Was also related. Patients undergoing percutaneous coronary angioplasty (PTCA) (Tahara et al . (1991) Metab. Clin. Exp . 40 : 1235-1237; Sanjay et al . (1991) Circulation 84 (Suppl. 4) : 726) In patients with pulmonary hypertension (Miyauchi et al . (1992) Jpn . J. Pharmacol ., 58 : 279P; Stewart et al . (1991) Ann. Internal Medicine , 114 : 464-469), increased levels of circulating endothelin were observed. It was. Thus, there are human clinical data supporting the correlation between elevated endothelin levels and many disease states.

Endothelin agonists and antagonists Endothelin is associated with certain disease states and has been suggested in many physiological effects to impair or enhance endothelin-related activities such as endothelin receptor interaction and vasoconstrictor activity The compounds that can be of interest are interesting. Compounds showing endothelin antagonist activity have been identified. For example, referred to as BE-18257B Streptomyces misakiensis fermentation production organisms, it has been confirmed that the ET _A receptor antagonist. BE-18257B is a cyclic pentapeptide cyclo (D-Glu-L-Ala-allo-D-Ile-L-Leu-D-Trp), and ¹²⁵ I-labeled endothelin- in cardiovascular tissue in a concentration-dependent manner. inhibits 1 binding (the _{IC 50,} 1.4 [mu] M in aortic smooth muscle, 0.8 [mu] M in ventricle membranes, 0.5μM in cultured aortic smooth muscle cells), the tissue ET _B receptors predominate, Concentrations below 100 μM do not inhibit receptor binding.

Acting as cyclo (D-Asp-Pro-D -Val-Leu-D-Trp) (BQ-123) and cyclic penta peptides related to BE-18257B, such as is synthesized, ET _A receptor antagonists (See US Pat. No. 5,114,918 to Ishikawa et al; see also EP A1 0 436 189 (October 7, 1991) to BANYU PHARMACEUTICAL CO., LTD). In the test measuring the inhibition by these cyclic peptides on the binding of endothelin-1 to endothelin-specific receptors, these cyclic peptides are preferentially shown to bind to the ET _A receptor. Other peptide and non-peptide ET _A antagonists have also been identified (e.g., Nos. 5,352,800, No. 5,334,598, No. 5,352,659, No. 5,248,807, No. 5,240,910, No. 5,198,548, No. 5,187,195, No. 5,082,838). Other cyclic pentapeptides, acyltripeptides, hexapeptide analogs, certain anthraquinone derivatives, indanecarboxylic acids, certain N-pyriminyl benzenesulfonamides, certain benzenesulfonamides And certain naphthalenesulfonamides (Nakajima et al ., (1991) J. Antibiot ., 44 : 1348-1356; Miyata et al ., (1992) J. Antibiot. , 45 : 74-8; Ishikawa et al ., (1992) J. Med . Chem ., 35 : 2139-2142; US Pat. No. 5,114,918 to Ishikawa et al .; EP A1 0 436 189 (October 7, 1991) to BANYU PHARMACEUTICAL CO., LTD. Canadian patent application 2067288; Canadian patent application 2071193; US patent 5208243; US patent 5270313; US patent 5612359; US patent 5514696; US patent . 378 715 No.; Cody et al (1993) Med.Chem.Res , 3:.. 154-162; Miyata et al (1992) J.Antibiot, 45:.. 1041-1046; Miyata et al (1992) J. Antibiot. , 45 : 1029-1040; Fujimoto et al. (1992) FEBS Lett. , 305 : 41-44; Oshashi et al . (1002) J. Antibiot. , 45 : 1684-1685; EP A 1 0 496 452 ; Clozel et al (1993) Nature , 365:.. 759-761; International Patent application WO 93/08799; Nishikibe et al (1993 ) Life Sci, 52:.. 717-724; and Benigni et al (1993) Kidney Int ., 44 : 440-444).

  In addition, many sulfonamides that are endothelin antagonists are disclosed in US Pat. Nos. 5,464,853, 5,594,021, 5,591,661, 5,571,821, 5,146,691, International PCT application WO 96/31492 and International PCT application WO 97/27979. Are listed.

Generally, confirmation compounds in an in vitro assay, with activity as ET _A antagonists at a concentration of about 50~100μM following levels. Many such compounds have also been shown to have activity in in vivo animal models.

Given the many physiological effects of endothelin antagonists and agonists endothelin as therapeutic agents and their relevance to certain diseases, endothelin is thought to play a very important role in their pathophysiological state. (Eg Saito et al . (1990) Hypertension 15 : 734-738; Tomita et al . (1989) N. Engl . J. Med ., 321 : 1127; Kurihara et al. (1989) J. Cardiovasc. Pharmacol. , 13 (Suppl . 5) : S13-S17; Doherty (1992) J. Med . Chem ., 35 : 1493-1508; Morel et al . (1989) Eur. J. Pharmacol. , 167 : 427-428 ). Obtaining more detailed knowledge about the function and structure of endothelin peptides requires a better understanding of the progression and treatment of such conditions. The use of these compounds for such applications requires stable formulations of these compounds in a pharmaceutically acceptable medium.

Compounds that exhibit activity at IC ₅₀ or EC ₅₀ concentrations of 10 ^-4 or less in standard in vitro assays that evaluate endothelin antagonist activity or agonist activity have been found to be pharmacologically useful. (For example, see US Pat. Nos. 5,352,800, 5,334,598, 5,352,659, 5,248,807, 5,240,910, 5,1985, 5,187,195, and 5082838). Due to its activity, such compounds may cause hypertension such as peripheral circulatory failure, heart disease such as angina, cardiomyopathy, atherosclerosis, myocardial infarction, pulmonary hypertension, vasospasm, vascular restenosis, Raynaud's disease, brain Stroke such as arterial spasm, cerebral ischemia, late phase cerebral spasm after subarachnoid hemorrhage, asthma, bronchoconstriction, renal failure, especially renal failure after ischemia, cyclosporine nephrotoxicity such as acute renal failure, colitis, As well as other inflammatory diseases, endotoxin shock caused by or associated with endothelin, and other diseases where endothelin has been suggested. As mentioned above, many of the compounds, especially the sulfonamide compounds, are potent endothelin antagonists and are therefore ideal clinical candidates. For clinical use, stable formulations and formulations suitable for various routes of administration are required.

  There are certain disadvantages to existing methods for producing such sulfonamides. For example, it is known that at certain stages of the synthetic pathway, dimerization of the intermediate occurs resulting in a decrease in yield and purity. Second, since the compound is hydrophobic, it is difficult to purify, and typically it is necessary to use impractical means such as preparative HPLC or column chromatography. Finally, existing methods are limited to the production of hydrophobic free sulfonamides, which are difficult to formulate into aqueous pharmaceutical compositions. If a metal hydroxide or methoxide is used to convert the free sulfonamide to a useful salt of an alkali metal, the compound may decompose.

Accordingly, it is an object of the present invention to provide a formulation of a compound that has the ability to modulate the biological activity of one or more endothelin peptides. Another object of the present invention is to provide a formulation of compounds having use as specific endothelin antagonists. Still another object of the present invention to use a formulation of a compound that inhibits the interaction of ET _A receptors or ET _B receptors specifically or greater and endothelin interact. Such formulations should be useful as therapeutic agents for treating endothelin mediated diseases and disorders. Furthermore, there is a need in the art for a practical and efficient method for producing the desired sulfonamide salt.

Summary of the Invention
Salts of Sulfonamide Compounds Sulfonamide derivatives used in the formulations and methods provided in the present invention, and methods for producing sulfonamide derivatives are provided. The sulfonamide derivative is useful as an endothelin receptor antagonist. Of interest are pharmaceutically acceptable derivatives such as salts, esters, acids and bases, solvates, hydrates and prodrugs of sulfonamides. In particular, a derivative of a neutral sulfonamide compound is provided that provides a formulation with unexpectedly higher stability than a formulation containing the corresponding neutral compound. Preferred are salts, particularly alkali metal salts, and more preferred are sodium salts. These include, but are not limited to, sodium bicarbonate, where the resulting product is the sodium salt, and salts made from sodium compounds, such as disodium hydrogen phosphate, where the resulting compound is the sodium hydrogen phosphate salt. It is not something. Most preferred are the sodium salts of each compound.

  Salt derivatives include alkali metal and alkaline earth metal salts such as, but not limited to, sodium, potassium, lithium, calcium and magnesium salts; zinc salts, copper salts, gold salts Transition metal salts such as salts and silver salts and other metal salts such as aluminum salts; but not limited to ammonium salts and substituted ammonium salts and organic amine salts such as hydroxyalkylamines and alkylamines Cationic and polyvalent cationic counterion salts; salts of mineral acids such as but not limited to hydrochloride and sulfate; acetate, lactate, malate, tartrate, citric acid Acid salts, ascorbate, succinate, butyrate, valerate and fumarate (but these It is intended to be constant not), and the like salts of organic acids, but is not intended to be limited thereto. Corresponding esters of either acid are also contemplated in the present invention.

  Preferred salts include acetates such as trifluoroacetate, N, N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N -Benzylphenethylamine, 1-parachlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris (hydroxymethyl) aminomethane, aluminum, calcium, lithium, magnesium, potassium, Examples include sodium hydrogen phosphate, disodium phosphate, sodium, zinc, barium, gold, silver and bismuth salts. In the present invention, alkali metal salts, particularly sodium salts are preferred.

（Ｉ） The sulfonamides from which derivatives, in particular salts, preferably sodium salts, are prepared have the structure of formula I

(I)

  Such sulfonamides include US Pat. Nos. 5,464,853, 5,590,401, 5,5961,55,181,55,461,5,464,53, co-owned and co-pending US patent application 08/721183, as well as internationally owned international applications. PCT application publications WO 96/31492 and WO 97/27979.

In certain embodiments, those sulfonamides are selected, provided that the salt is 4-chloro-3-methyl-5- (2- (6-methylbenzo [d] [1,3] dioxole- 5-yl) acetyl) -3-thienylsulfonamido) isoxazole sodium salt; N ^2- (3-cyanomethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5- Isoxazolylsulfamoyl) -2-thiophenecarboxamide sodium salt; N ^2- (3-acetyloxymethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-iso oxazolidone Rusuru sulfamoyl) -2-thiophenecarboxamide sodium salt; and ^N 2 - (3- hydroxymethyl-2,4,6-trimethylphenyl) - - not (4-chloro-3-methyl-5-isoxazolyl Rusuru sulfamoyl) -2-thiophenecarboxamide, sodium salt.

In particular, the sulfonamides of formula (I) are those in which Ar ¹ is substituted or unsubstituted alkyl, or 5- or 6-membered substituted or unsubstituted aromatic or heteroaromatic rings, in particular 3- or 5 -Isoxazolyl and pyridazinyl, further, for example, thiazolyl such as 2-thiazolyl, pyrimidinyl such as 2-pyrimidinyl, or substituted benzene groups such as aryloxy-substituted benzene groups, or bicyclic or tricyclic carbocyclic or heterocyclic It is a ring. For certain embodiments, Ar ¹ is selected from the group consisting of:

In the above, R is H, NH ₂ , halide, pseudohalide, alkyl, alkylcarbonyl, formyl, aromatic group or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio , Haloalkyl, haloaryl, carbonyl; the aryl and alkyl moieties in them are unsubstituted or any of the aforementioned groups and have from about 10 to 12, preferably from 1 to 5 or 6 carbon atoms It is substituted with a straight or branched chain. R is preferably H, NH ₂ , halide, CH ₃ , CH ₃ O or another aromatic group.

Ar ² is a group such that the resulting sulfonamide inhibits endothelin peptide binding to the endothelin receptor by 50% at a concentration of less than about 100 μM compared to binding in the absence of sulfonamide. . However, Ar ¹ is N- (5-isoxazolyl) or N- (3-isoxazolyl) when the isoxazole is not 4-halo-isoxazole or 4-higher alkyl (C ₈ -C ₁₅ ) -isoxazole. In some cases, Ar ² is not phenyl or naphthyl, or the compound is 4-biphenyl, which is unsubstituted at the 2- or 6-position on the phenyl group linked to the sulfonamide.

Specifically, Ar ² is a substituted or unsubstituted group selected from the groups according to the above assumptions, such as naphthyl, phenyl, biphenyl, quinolyl, styryl, thienyl, furyl, isoquinolyl, pyrrolyl, benzofuryl, pyridinyl, Examples include, but are not limited to, thianaphthyl, indolyl, alkyl, and alkenyl. Obviously, the positions indicated for substituents such as sulfonamide groups may vary. Thus, for example, the compounds include the group comprising thiophene-3-sulfonamides and thiophene-2-sulfonamides.

The sulfonamide is a substituted or unsubstituted monocyclic or polycyclic aromatic or heteroaromatic sulfonamide, and examples thereof include benzenesulfonamides, naphthalenesulfonamides, and thiophenesulfonamides. Particularly preferred sulfonamides are N-isoxazolyl sulfonamides. More preferred among such sulfonamides are those in which Ar ² has one ring, multiple rings or fused rings, typically 2 or 3 rings, One or two atoms.

In a preferred sulfonamide derivative (preferably a sodium salt), Ar ² represents thienyl, furyl, pyrrolyl or a group such as benzofuryl, thianaphthyl or indolyl which are derivatives or analogs of thienyl, furyl or pyrrolyl groups as described below or 4- A biphenyl group; Ar ¹ is preferably N- (5-isoxazolyl) or N- (3-isoxazolyl). The most interesting here are salts, in particular sodium salts, such as sodium salts of compounds in which Ar ² is a thienyl, furyl, pyrrolyl group substituted with phenylacetyl. Preferred as salts, particularly sodium salts, are those in which Ar ² is thienyl, furyl or pyrrolyl, especially those in which Ar ² is substituted with phenylacetyl and Ar ¹ is isoxazole. .

In certain embodiments, the preferred salt is 4-chloro-3-methyl-5- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamide. ) isoxazole sodium ^salt; N 2 - (3- cyanomethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolyl Rusuru sulfamoyl) -2-thiophenecarboxamide Sodium salt; N ^2- (3-acetyloxymethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl) -2-thiophenecarboxamide sodium salt; and ^N 2 - (3- hydroxymethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5- Isoo Is selected from the sub sledding Rusuru sulfamoyl) -2-thiophenecarboxamide, sodium salt.

  More preferred sulfonamide salts include N- (4-chloro-3-methyl-5-isoxazolyl) -2- [2-methyl-4,5- (methylenedioxy) phenylacetyl] thiophene-3-sulfonamide. Sodium salt (in this specification 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfone Amide) isoxazole sodium salt).

Sulfonamides Sulfonamide compounds as described herein and derivatives and formulations of the compounds are also provided. The sulfonamide compound is active as an endothelin receptor antagonist and provides higher tolerability compared to sulfonamides known in the art. Preferred sulfonamide compounds are those of the following formula or pharmaceutically acceptable derivatives such as alkali metal salts (particularly sodium salts) of the compounds.

Ｒ^３およびＲ^４は独立に、水素、ハロゲン、シアノ、シアノアルキル、Ｃ（Ｏ）Ｒ^４１、アルキル、アルケニル、シクロアルキルおよびアリールからなる群から選択されるか、あるいは一体となってアルキレンを形成しており；
ＷはＯ、ＮＨまたはＣＨ_２であり；
Ｒ^５、Ｒ^６およびＲ^７はそれぞれ独立に、下記の（ｉ）または（ｉｉ）であり、ただし、Ｒ^５、Ｒ^６およびＲ^７のうちで水素であるのは１個以下であり；
（ｉ）Ｒ^６が水素、不飽和アルキル、水酸基、不飽和アルコキシ、Ｃ（Ｏ）Ｒ^４１、カルバモイルオキシもしくはアルコキシカルボニルオキシであり；
Ｒ^５およびＲ^７がそれぞれ独立に、水素、不飽和アルキル、水酸基、Ｃ（Ｏ）Ｒ^４１、カルバモイルオキシおよびアルコキシカルボニルオキシであるか；または Wherein Ar ¹ is isoxazolyl and Ar ² has the structure of the formula:

R ³ and R ⁴ are independently selected from the group consisting of hydrogen, halogen, cyano, cyanoalkyl, C (O) R ⁴¹ , alkyl, alkenyl, cycloalkyl and aryl, or together form an alkylene And
W is O, NH or CH ₂ ;
R ⁵ , R ⁶ and R ⁷ are each independently the following (i) or (ii), provided that no more than one of R ⁵ , R ⁶ and R ⁷ is hydrogen;
(I) R ⁶ is hydrogen, unsaturated alkyl, hydroxyl, unsaturated alkoxy, C (O) R ⁴¹ , carbamoyloxy or alkoxycarbonyloxy;
R ⁵ and R ⁷ are each independently hydrogen, unsaturated alkyl, hydroxyl, C (O) R ⁴¹ , carbamoyloxy and alkoxycarbonyloxy; or

(Ii) if at least one of R ³ and R ⁴ is not hydrogen, any two can form alkylenedioxy, the other is selected as described in (i);
R ⁴⁵ is alkyl, C (O) R ⁴¹ , (CH ₂ ) _x OH and CH (OH) (CH ₂ ) _x CH ₃ (x is 0 to 6), S (O) _n R ⁴¹ (n Is selected from the group consisting of C (= NR ⁴³ ) R ⁴¹ ;
R ⁴¹ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylarylamino, aryl Sulfonylalkylamino or arylsulfonylarylamino;
R ⁴³ is selected from hydroxyl, alkoxy, alkyl and aryl;

R ⁴¹ and R ⁴³ are unsubstituted or substituted by one or more substituents selected from Y; Y is alkoxy, halide, pseudohalide, carboxyl, alkoxycarbonyl, aryloxycarbonyl or hydroxyl group Yes; provided that the compound is N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfonamide, N- (4- Chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl) phenylacetyl-3-thiophenesulfonamide, N- (3,4-dimethyl-5-isoxazolyl) -2-[(2 , 4,6-trimethylphenoxy) carbonyl] thiophene-3-sulfonamide, N- (4-chloro-3- Til-5-isoxazolyl) -2-[(2,4,6-trimethylphenoxy) carbonyl] thiophene-3-sulfonamide and N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(2 , 4,6-trimethylphenoxy) carbonyl] thiophene-3-sulfonamide.

  In another embodiment, the sulfonamide is wherein the compound is N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-methoxy-2,4,6-trimethylphenylaminocarbonyl) thiophene- 3-sulfonamide, N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-hydroxy-2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfonamide, N- (4 -Chloro-5-methyl-3-isoxazolyl) -2- (3-hydroxy-2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfonamide and N- (3,4-dimethyl-5-isoxazolyl) -2- (3-methoxy-2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfonamide It is further selected to provide a condition that there be no.

  Thus, the sulfonamides provided in the present invention are 2-acyl-3-thiophene sulfonamides. In this case, corresponding 3-acyl-2-thiophenesulfonamides are also conceivable. Also provided are formulations and salts of the above compounds as described herein.

Sulfonamide and Sulfonamide Salt Formulations Formulations of sulfonamide compounds having activity as endothelin antagonists for administration to mammals such as humans are provided. In particular, formulations are provided for parenteral administration, oral administration, transdermal administration, as well as other suitable routes of administration, such as intramuscular, intravenous and subcutaneous administration. The formulation provides a means of reliably administering an effective amount of the compound.

  Of interest are formulations of pharmaceutically acceptable derivatives such as salts, esters, acids and bases, solvates, hydrates and prodrugs of the sulfonamides. In particular, derivatives of neutral sulfonamides are provided that give formulations that are considerably more stable than formulations containing the corresponding neutral compounds. Preference is given to salts, in particular alkali metal salts, more preferably sodium bicarbonate, in which the resulting product is a sodium salt, and disodium hydrogen phosphate, in which the resulting product is a sodium hydrogen phosphate salt, etc. Sodium salts such as salts produced from (but not limited to) sodium compounds. Most preferred are the sodium salts of each compound.

  The formulation is a composition suitable for administration by any desired route, and is a solution, suspension, emulsion, tablet, dispersible tablet, pill, capsule, powder, dry powder for inhaler, sustained release formulation, There are aerosols for nasal and respiratory administration, transdermal administration and any other suitable route plaster. The composition should be suitable for oral administration, parenteral administration by injection such as subcutaneous, intramuscular or intravenous administration as an aqueous or oily solution or emulsion for injection, transdermal administration and other specific routes. I must.

  Also provided are lyophilized powders of sulfonamide derivatives, methods for their preparation and formulations comprising regenerated lyophilized powders. Powdered vials and ampoules and syringes and other suitable containers are also provided.

Further, the most preferred formulation for use in the methods provided in the present invention are compounds which are ET _A selective, i.e. at a much lower concentration than interaction with the ET _B receptor (IC _50, of at least about 10 times, preferably not including 100-fold lower) ET _a receptor compounds that interact. In particular, less than about the ET _A 10 [mu] M, preferably below 1 [mu] M, more preferably it interacts with _{an IC 50} of less than 0.1 [mu] M, compound interacts with about 10 [mu] M _{IC 50 of} greater than the ET _B, or ET _B with less than about 10 [mu] M, preferably below 1 [mu] M, more preferably it interacts with _{an IC 50} of less than 0.1 [mu] M, compounds that interact with about 10 [mu] M _{IC 50 of} greater than the ET _a is preferred.

Preferred formulations, compounds that bind compound is ET _B receptor selective or an _{IC 50} of less than about 1μM and ET _B receptors are also included. ET _B selective compounds, it ET _A interact with ET _B receptors at low _{IC 50} concentration of about 10 times more than the concentration that interact with the receptor.

  The formulations provided herein are for administration by a specific route and contain an effective concentration of a pharmaceutically acceptable salt of the above compound. Heart diseases such as hypertension, stroke, cardiovascular disease, myocardial infarction, pulmonary hypertension, erythropoietin-mediated hypertension, respiratory diseases, inflammatory diseases such as asthma, ocular diseases such as bronchoconstriction, glaucoma and retinal perfusion failure Gastrointestinal disease, renal failure, endotoxin shock, menstrual disorders, obstetric conditions, wounds, anaphylactic shock, hemorrhagic shock and endothelin-mediated physiological responses are suggested or involved in vasoconstriction or endothelin antagonists or products Also provided are formulations that administer an amount effective to treat other diseases whose symptoms can be alleviated by administering an agonist.

  In one embodiment, the formulations are capsules and tablets comprising the sodium salt of the sulfonamide described herein. Preferred formulations are those that administer an amount effective to treat hypertension or renal failure. The effective amount and concentration is effective to ameliorate any symptom of any of the above disorders.

  In a more preferred embodiment, the formulation is a solid formulation or gel, preferably a capsule or tablet. In one preferred embodiment, the formulation is an effective amount, typically about 10-100% by weight, preferably about 50-95%, more preferably about 75-85%, most preferably about 80-85%. % Of one or more sodium hydrogenphosphate or sodium salt, preferably sodium salt of one or more sulfonamide compounds of formula I; about 0-25%, preferably 8-15%, such as lactose or microcrystalline cellulose diluted About 0-10%, preferably about 3-7% of modified starch or cellulose polymer, especially croscarmellose sodium (croscarmellose sodium NF is named AC-DI-SOL) Commercially available (FMC Corporation, Philadelphia, PA) and cross-linked carboxymethyl such as sodium starch glycolate Disintegrating agents such as cellulose sodium; and, 0-5%, a capsule preferably containing a lubricant such as 0.1% to 2% of magnesium stearate, talc and calcium stearate.

  Disintegrants such as croscarmellose sodium and sodium starch glycolate disintegrate the cellulosic substrate rapidly after dissolution of the coating polymer and immediately release the active agent. In all embodiments, the exact amounts of active and adjunct ingredients can be determined empirically and depends on the route of administration and the disorder being treated. Solid formulations for administration as tablets are also contemplated by the present invention.

  A preferred formulation is prepared from a sterile lyophilized powder containing the sodium salt of sulfonamide. A freeze-dried powder and a method for preparing the powder are also provided in the present invention.

  In one embodiment, the composition is provided in the form of a lyophilized solid comprising one or more sodium hydrogen phosphates or sodium salts, preferably sodium salts, of one or more sulfonamide compounds of formula I. The following components are also included.

Buffering agents such as sodium or potassium phosphate or citrate;
LABRASOL (polyethylene glycol-8 caprylic acid / capric acid glycerides sold by Gattefosse SA (France)), dimethyl sulfoxide (DMSO), bis (trimethylsilyl) acetamide, ethanol, propylene glycol (PG) or polyvinylpyrrolidone (PVP) Solubilizing agents; and sugars such as sorbitol or glucose and other such carbohydrates (typically about 1% to 20%, preferably about 5% to 15%, more preferably about 5% to 10% range).

  For administration, the lyophilized powder is admixed with a suitable carrier such as phosphate buffered saline (typically about 100-500 mg, preferably 250 mg single dose formulation or multiple dose formulation is obtained). ).

  In other preferred embodiments where the formulation is for parenteral administration, the composition comprises one or more sodium hydrogen phosphate or sodium salt, preferably sodium salt of one or more sulfonamide compounds of formula I; A buffer such as potassium phosphate or citrate; and a sugar such as sorbitol or glucose are included. In one preferred embodiment described in detail herein, the formulation comprises one or more sodium salts of sulfonamide compounds of formula I; sodium phosphate buffer; and glucose. Glucose can be added in the form of a sterile glucose solution readily available from suppliers known to those skilled in the art.

Methods of modulating the interaction of endothelin peptides with ET _A and / or ET _B using a method such formulations use is provided. The method comprises the step of contacting the receptor with one or more pharmaceutically acceptable salts of a sulfonamide, preferably sodium of the formulated sulfonamide, prior to, simultaneously with, or after contacting the receptor with the endothelin peptide. This is done by contacting with salt.

  Methods are provided for inhibiting the binding of endothelin peptides to endothelin receptors. The method is performed by contacting the receptor with a formulation of a pharmaceutically acceptable salt of one or more provided compounds simultaneously with, prior to, or after contacting the receptor with the endothelin peptide.

  Methods of treatment for hypertension, asthma, shock, high intraocular pressure, glaucoma, retinal perfusion failure (but not limited to) and some form of endothelin peptide mediated disorder or endothelin involving vasoconstriction Methods of treating disorders that are ameliorated by administering an antagonist or agonist are provided.

  In particular, there is provided a method of treating endothelin-mediated disorders by administering an effective amount of a pharmaceutically acceptable salt of the sulfonamide as described above, a prodrug of the sulfonamide or other suitable derivative. Specifically, administration of an effective amount of one or more formulations containing a pharmaceutically acceptable salt of a compound provided by the present invention in a pharmaceutically acceptable carrier results in hypertension, cardiovascular disease. , Heart diseases such as myocardial infarction, pulmonary hypertension, erythropoietin-mediated hypertension, respiratory and inflammatory diseases such as asthma, bronchoconstriction, eye diseases, gastrointestinal diseases, renal failure, endotoxin shock, menstrual disorders, obstetrics Methods are provided for the treatment of endothelin-mediated disorders such as conditions, wounds, anaphylactic shock, hemorrhagic shock and other diseases where an endothelin-mediated physiological response is suggested. Preferred treatment methods are those for hypertension and renal failure.

The most preferred method of treatment, less than about 10 [mu] M, preferably less than about 5 [mu] M, more preferably less than about 1 [mu] M, more preferably less than 0.1 [mu] M, most preferably with _{an IC 50} of less than 0.05 [mu] M, endothelin-1 and ET _A receptor The formulation contains one or more compounds that inhibit the interaction with the body. Other preferred methods are those pharmaceutically acceptable salts of a pharmaceutically acceptable salt or ET _B selective one or more compounds which is of one or more compounds that are ET _A selective are included in the formulation is there. Wherein the compound is ET _A selective are for treatment of disorders such as hypertension, wherein the compound is ET _B selective are for treatment of disorders such as asthma requiring bronchodilation.

  In the implementation of the method, hypertension, cardiovascular disease, heart disease such as myocardial infarction, respiratory disease such as asthma, inflammatory disease, ocular disease, gastrointestinal disease, renal failure, immunosuppressant-mediated renal vasoconstriction, erythro For oral, intravenous, topical, and topical administration for the treatment of poietin-mediated vasoconstriction, endotoxin shock, anaphylactic shock, hemorrhagic shock, pulmonary hypertension, and other diseases that suggest endothelin-mediated physiological responses A formulated, effective amount of a formulation comprising a therapeutically effective concentration of a pharmaceutically acceptable salt of the compound is administered to a patient exhibiting one or more symptoms of the disorder. The amount is effective to ameliorate or eliminate one or more symptoms of the disorder.

  Methods for identifying and isolating endothelin receptor subtypes are also provided. In particular, methods are provided for detecting, identifying and isolating endothelin receptors using the disclosed compounds. In particular, methods are provided for detecting, identifying and isolating endothelin receptors using the compounds provided herein.

  Further provided are methods of identifying compounds suitable for use in the treatment of a particular disease based on preferential affinity for a particular endothelin receptor subtype.

Packaging material: a preparation provided by the present invention effective for improving symptoms of endothelin-mediated disorder, antagonizing the effect of endothelin or inhibiting the binding of endothelin peptide to ET receptor, and contained in the packaging material A formulation comprising a compound having an IC ₅₀ of less than about 10 μM; and said formulation is used for antagonizing the effects of endothelin, treating endothelin-mediated disorders or inhibiting the binding of endothelin peptides to ET receptors An article of manufacture having a label indicating is provided.

Formulation Methods A method for producing an alkali metal salt of a hydrophobic free sulfonamide is also provided. The method includes dissolving a free sulfonamide in an organic solvent; washing the dissolved free sulfonamide with a saturated solution of an alkali metal salt; and recovering the alkali metal salt of the sulfonamide from the organic layer. is there. A preferred organic solvent is ethyl acetate or THF. Preferred alkali metals are sodium, potassium, calcium or magnesium, with sodium being most preferred. According to a preferred embodiment, the method uses saturated sodium bicarbonate or sodium carbonate solution as the alkali metal salt solution. Sodium bicarbonate solution is most preferred.

  Preferably for recovery, dehydrating the organic solvent solution of the salt; concentrating the salt; crystallizing the salt in one or more non-water miscible organic solvents; and sulfonamide salt by filtration There is a stage to recover. Preferred non-water miscible organic solvents are methylene chloride and ether. The method provided by the present invention may further include a step of purifying the sulfonamide salt after recovery.

One embodiment of the method is 4-chloro-3-methyl-5- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole Sodium salt; N ^2- (3-cyanomethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl) -2-thiophenecarboxamide sodium salt ; ^N 2 - (3- acetyloxymethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolyl Rusuru sulfamoyl) -2-thiophenecarboxamide sodium salt; and ^N 2 - (3- hydroxymethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolyl Luz Famoiru) is particularly useful for the production of 2-thiophene carboxamide sodium salt.

  Provided are alkali metal salts of sulfonamides, especially such salts obtained by the process of the present invention. A preferred such sulfonamide salt is 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfone. Amido) isoxazole sodium salt.

Detailed Description of the Preferred Embodiment
Definition

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited herein are hereby incorporated by reference.

  As used herein, endothelin (ET) peptides include peptides having substantially the amino acid sequence of endothelin-1, endothelin-2 or endothelin-3 and acting as potent endogenous vasoconstrictor peptides Is included.

  As used herein, an endothelin-mediated condition is a condition caused by abnormal endothelin activity or a condition where a compound that inhibits endothelin activity has therapeutic use. Such diseases include hypertension, cardiovascular disease, asthma, inflammatory diseases, eye diseases, menstrual disorders, obstetric conditions, gastrointestinal disorders, renal failure, pulmonary hypertension, endotoxin shock, anaphylactic shock or hemorrhagic shock. However, it is not limited to these. Endothelin-mediated conditions also include conditions caused by therapy with agents that increase endothelin levels, such as erythropoietin and immunosuppressants.

  As used herein, an effective amount of a compound in treating a particular disease refers to an amount that only ameliorates or somehow alleviates the disease-related symptoms. Such amounts can be administered in a single dose or can be administered according to an effective method of administration. The amount may cure the disease, but typically it is administered to improve the symptoms of the disease. Typically, repeated administration is necessary to obtain the desired symptom improvement.

  As used herein, an endothelin agonist is a compound that enhances or exhibits a bioactivity associated with or possessed by an endothelin peptide.

As used herein, an endothelin antagonist is a compound such as an agent or antibody that inhibits endothelin-stimulated vasoconstriction and spasm and other endothelin-mediated physiological responses. The antagonist is thought to act by interfering with the interaction of endothelin with endothelin-specific receptors, or by interfering with physiological responses to endothelin isopeptides such as vasoconstriction or the biological action of the substance. It is done. Accordingly, as used herein, endothelin antagonists, or interfere with vasoconstriction other response by endothelin stimulation, or as one skilled in the art will evaluated by known assays, endothelin, such as ET _A receptors It interferes with the interaction between specific receptors and endothelin.

The effectiveness of potential agonists and antagonists can be assessed using methods known to those skilled in the art. For example, endothelin agonist activity can be confirmed by the ability to stimulate vasoconstriction of isolated rat thoracic aorta or portal annulus (Borges et al . (1989) "Tissue selectivity of endothelin" Eur. J. Pharmacol ., 165 : 223-230). Endothelin antagonist activity can be assessed by its ability to interfere with endothelin-induced vasoconstriction. An example assay is given in the examples. As noted above, the preferred IC ₅₀ concentration range is shown with reference to an assay in which a test compound is incubated at 4 ° C. with cells having an ET receptor. There are data shown for assays in which the incubation step is carried out at a less favorable 24 ° C. By comparison, it can be seen that their concentrations are slightly higher than those measured at 4 ° C.

As used herein, endothelin's bioactivity or bioactivity includes activities induced, enhanced or influenced by endothelin in vivo . It further includes the ability to bind to specific receptors and the ability to elicit functional responses such as vasoconstriction. It can be evaluated in an in vivo assay or an in vitro assay as exemplified herein. Related activities include, but are not limited to, vasoconstriction, vasorelaxation and bronchodilation. For example ET _B receptors appear to be expressed in vascular endothelial cells may be interposed such a response vascular ward intestine and others. On the other hand, ET _A receptor is endothelin-1-specific is located on the smooth muscle is associated with vasoconstriction. Assays known to those skilled in the art of measuring or detecting such activity can be used to assess such activity (eg, Spokes et al . (1989) J. Cardiovasc. Pharmacol ., 13 ( Suppl. 5) : S191- S192 ; Spinella et al . (1991) Proc. Natl. Acad. Sci. USA , 88 : 7443-7446; Cardell et al . (1991) Neurochem. Int ., 18 : 571-574; As well as the examples herein).

As used herein, bioavailability refers to the rate and extent of absorption. Methods for determining bioavailability are known to those skilled in the art. For example, the bioavailability of any of the compounds described herein is empirical by administering the compound to an animal, then collecting blood over time and measuring the blood concentration of the compound. Can be requested. In vivo half-life (t _1/2 ) is defined as the time it takes for the concentration of a compound in the blood to decrease by half. The area under the curve for intravenous administration can be estimated and used to estimate the area under the curve for oral administration to obtain bioavailability data (eg, Milo Gibal (1991) Biopharmaceutics and Pharmacology, 4th edition (Lea and Sediger)).

As used herein, efficacy refers to the maximum effect that a compound can provide. Efficacy can be determined by methods known to those skilled in the art. For example, it can be determined by the nature of the compound and its receptor-agonist system and is reflected in the horizontal portion of the concentration-effect curve. In vivo potency refers to potency measured in an animal model. For example, the in vivo efficacy of the compounds described herein can be determined by amelioration of hypoxia-induced pulmonary hypertension in rats. In that context, in vivo efficacy refers to the ability of the compound to restore elevated pulmonary pressure to normal (see DiCarlo et al . (1995) Am . J. Physiol ., 269 : L690-L697).

As used herein, IC ₅₀ refers to the amount, concentration or volume of a particular compound that gives 50% inhibition of maximal responses, such as binding of endothelin to tissue receptors, in assays that measure such responses. Point to.

As used herein, EC ₅₀ is the dose, concentration of a particular test compound that elicits a dose-dependent response at 50% of the maximum expression of that particular response elicited, aroused or enhanced by a particular test compound. Or refers to the amount.

As used herein, the ET _A selective sulfonamide refers to a sulfonamide showing the ET _B receptor with low _{IC 50} of about 10 times or more with respect to ET _A receptors compared.

As used herein, ET _B The selective sulfonamide refers to a sulfonamide showing the ET _A receptor and lower _{IC 50} of about 10 times or more with respect to ET _B receptors compared.

  As used herein, pharmaceutically acceptable salts, esters, hydrates, solvates and other derivatives of the compounds can be obtained by those skilled in the art using known methods for such derivatization. Such as salts, esters and other derivatives which can be manufactured and give compounds which can be administered to animals or humans with substantially no toxic effect, and which are pharmaceutically active or prodrugs . Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal salts such as sodium, potassium, lithium, calcium and magnesium salts; zinc salts, copper Transition metal salts such as salts and aluminum salts; polyvalent cation counterion salts such as but not limited to ammonium salts and substituted ammonium salts and organic amine salts such as hydroxyalkylamines and alkylamines; hydrochlorides And inorganic acid salts such as but not limited to sulfate, acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate And salts of organic acids such as fumarate, but are not limited thereto. Corresponding esters are also envisaged in the present invention.

  Preferred pharmaceutically acceptable salts include N, N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-parachlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris (hydroxymethyl) aminomethane, aluminum, calcium, lithium, magnesium, potassium, sodium hydrogen phosphate, Examples include, but are not limited to, disodium phosphate, sodium, zinc, barium, gold, silver and bismuth salts. Sodium salts, particularly the sodium salt of each compound, are most preferred in the present invention.

As used herein, the term “sodium salts” refers to salts of sodium compounds where the counter ion includes Na ⁺ and may also include other ions such as HPO ₄ ²⁻ , when referred to as “sodium salts”. Specifically refers to salts where Na ⁺ is the counter ion (not sodium salts).

  As used herein, treatment means a method by which symptoms of a condition, disorder or disease are ameliorated or otherwise changed in an advantageous manner. Treatment also includes the pharmaceutical use of the composition of the invention, such as use as a contraceptive.

  As used herein, amelioration of a particular disorder symptom by administration of a particular pharmaceutical composition is a sustained or transient reduction (permanently) that may or may be associated with administration of the composition. Or temporary).

  As used herein, the term substantially pure is sufficiently homogenous and one skilled in the art such as thin layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography (HPLC) The standard analytical method used to assess purity appears to be free of readily detectable impurities, or is sufficiently pure and subject to further enzymatic activity It also means that no detectable change in physical and chemical properties such as bioactivity is likely to occur. Methods for purifying compounds to obtain substantially chemically pure compounds are known to those skilled in the art. However, a substantially chemically pure compound may be a mixture of stereoisomers. In such a case, it is considered that the specific activity of the compound may increase by further purification.

As used herein, bioactivity refers to the in vivo activity of a compound or the physiological response produced by in vivo administration of a compound, composition or other mixture. Thus, physiological activity includes therapeutic effects and pharmaceutical activity of such compounds, compositions and mixtures.

  As used herein, an increase in the stability of a formulation refers to a formulation measured by an assay known to those skilled in the art, such as high performance liquid chromatography, gas chromatography, etc., at a predetermined time after preparation of the formulation. It means that the percentage of active ingredient present is significantly higher than the percentage of active ingredient present in another formulation after the same period of time from formulation preparation. In that case, the former formulation is said to have increased stability compared to the latter formulation.

As used herein, a prodrug is a compound that undergoes metabolism or other transformation upon administration in vivo to form a physiologically, pharmaceutically or therapeutically active form of the compound. To obtain a prodrug, the pharmaceutically active compound is modified to regenerate the active compound during metabolic processes. Prodrugs may be manufactured with the aim of altering the metabolic stability or transport properties of a drug; reducing side effects or toxicity; improving the flavor of the drug; or altering other properties or properties of the drug it can. Knowing the pharmacological process and in vivo drug metabolism to know a pharmaceutically active compound, one skilled in the art can produce a prodrug of that compound (eg, Nogrady ( 1985) Medicinal Chemistry A Biochemical Approach ., Oxford University Press, New York, pp.388-392). For example, succinyl-sulfathiazole is a prodrug of 4-amino-N- (2-thiazolyl) benzenesulfonamide (sulfathiazole) that exhibits different transport properties.

  As used herein, an acid isotope means a group that is highly ionized at biological pH. Examples of suitable acid isosteres include sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl or heteroarylsulfonylcarbamoyl.

  As used herein, halo or halide refers to the halogen atoms F, Cl, Br and I.

  As used herein, a pseudohalide is a compound that exhibits substantially the same behavior as a halide. Such compounds can be used in the same manner as halides (X; X is a halogen such as Cl or Br) and can be treated similarly. Pseudohalides include, but are not limited to, cyanide, cyanate, thiocyanate, selenocyanate and azide.

  As used herein, haloalkyl is a lower group in which one or more hydrogen atoms are replaced by, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, and the like. Refers to an alkyl group.

  As used herein, alkyl means a straight or branched aliphatic hydrocarbon group, preferably having about 1 to 12 carbon atoms in the chain. Preferred alkyl groups are lower alkyl groups including alkyl having 1 to 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Alkyl groups can be unsubstituted or independently substituted with one or more groups such as, but not limited to, halo, carboxy, formyl, sulfo, sulfino, carbamoyl, amino and imino. Also good. Examples of alkyl groups are methyl, ethyl and propyl.

  As used herein, the term lower refers to alkyl, alkenyl and alkynyl groups having about 6 or fewer carbon atoms. It is also used to refer to an aryl or heteroaryl group having 6 or fewer atoms in the ring. Lower alkyl, lower alkenyl and lower alkynyl refer to carbon chains having less than about 6 carbon atoms. Preferred embodiments of the compounds provided herein having an alkyl moiety, an alkenyl moiety or an alkynyl moiety include a lower alkyl moiety, a lower alkenyl moiety and a lower alkynyl moiety.

  As used herein, alkenyl is an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight or branched, having from about 2 to about 10 carbon atoms in the chain. Means. Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups or lower alkenyl groups are bonded to a straight alkenyl chain. An alkenyl group can be unsubstituted or independently substituted with one or more groups such as, but not limited to, halo, carboxy, formyl, sulfo, sulfino, carbamoyl, amino and imino. Also good. Examples of alkenyl groups include ethenyl, propenyl and butenyl.

  As used herein, alkynyl is an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be linear or branched, having from about 2 to about 10 carbon atoms in the chain. means. Branched means that one or more lower alkyl groups, alkenyl groups or alkynyl groups are bonded to a linear alkynyl chain. An example of an alkynyl group is ethynyl.

  As used herein, aryl means an aromatic monocyclic or polycyclic hydrocarbon ring system having 3 to 15 or 16 carbon atoms, preferably 5 to 10 carbon atoms. Aryl groups include groups such as but not limited to phenyl, substituted phenyl, naphthyl, substituted naphthyl and the like, where the substituent is lower alkyl, halogen or lower alkoxy. Preferred aryl groups are lower aryl groups having less than 7 carbon atoms in the ring structure.

  As used herein, nomenclature such as alkyl, alkoxy, carbonyl, etc. is used as commonly understood by one of ordinary skill in the art. For example, as used herein, alkyl refers to a saturated carbon chain having one or more carbons, the chain being linear or branched, having a cyclic moiety, or cyclic. Can do. As used herein, alicyclic refers to a cyclic aryl group.

  As used herein, cycloalkyl refers to a saturated cyclic carbon chain. Cycloalkenyl and cycloalkynyl refer to cyclic carbon chains each having one or more unsaturated double or triple bonds. The cyclic portion of the carbon chain can have one ring or two or more fused rings.

  As used herein, cycloalkenyl means a non-aromatic mono- or polycyclic ring system having a carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Examples of monocyclic cycloalkenyl rings are cyclopentenyl or cyclohexenyl. Preferred is cyclohexenyl. An example of a polycyclic cycloalkenyl ring is norbornylenyl. A cycloalkenyl group may be independently substituted with one or more halo or alkyl.

  As used herein, “haloalkyl” refers to, but is not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, and the like, wherein one or more hydrogen atoms are replaced by halogen. Or a lower alkyl group.

  As used herein, “haloalkoxy” refers to RO— where R is a haloalkyl group.

As used herein, “carboxamide” is a group of the formula R _p CONH _{2 wherein} R is selected from alkyl or aryl, preferably lower alkyl or lower aryl, and p is 0 or 1 Point to.

  As used herein, “alkylaminocarbonyl” refers to —C (O) NHR where R is hydrogen, alkyl, preferably lower alkyl or aryl, preferably lower aryl.

  As used herein, “dialkylaminocarbonyl” is —C (O) NR′R, wherein R ′ and R are independently selected from alkyl or aryl, preferably lower alkyl or lower aryl. “Carboxamide” refers to a group of formula NR′COR.

  As used herein, “alkoxycarbonyl” refers to —C (O) OR where R is alkyl, preferably lower alkyl or aryl, preferably lower aryl.

As used herein, “alkoxy” and “thioalkoxy” refer to RO— and RS—, wherein R is alkyl, preferably lower alkyl or aryl, preferably lower aryl. As used herein, “haloalkoxy” refers to RO— where R is a haloalkyl group.
As used herein, “aminocarbonyl” refers to —C (O) NH ₂ .

  As used herein, cycloalkyl refers to a saturated cyclic carbon chain, and cycloalkenyl and cycloalkynyl refer to a cyclic carbon chain having one or more unsaturated triple bonds. The cyclic portion of the carbon chain can have one ring or two or more fused rings.

  As used herein, alkylenedioxy means an -O-alkyl-O- group in which the alkyl group is as previously described. By substituted analog of alkylenedioxy is meant alkylenedioxy in which one or both oxygen atoms are replaced by atoms that exhibit similar behavior or groups of atoms such as S, N, NH, Se, and the like. An example of a substituted alkylenedioxy group is ethylene bis (sulfanediyl). Alkylenethioxy is -S-alkyl-O-, -O-alkyl-S-, and alkylenedithioxy is -S-alkyl-S-.

  As used herein, heteroaryl means an aromatic monocyclic or fused ring system in which one or more carbon atoms in the ring system have been replaced by elements other than carbon, such as nitrogen, oxygen or sulfur. . Preferred cyclic groups have 1 or 2 fused rings, each ring being about 3 to about 7 members. As with “aryl groups”, heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include pyrazinyl, pyrazolyl, tetrazolyl, furyl, (2- or 3-) thienyl, (2-, 3- or 4-) pyridyl, imidazolyl, pyrimidinyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indolyl , Isoquinolinyl, oxazolyl and 1,2,5-oxadiazolyl. Preferred heteroaryl groups include 5-6 membered nitrogen containing rings such as pyrimidinyl.

  As used herein, alkoxycarbonyl means an alkyl-O-CO- group. Examples of alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.

As used herein, carbamoyl means —CONH ₂ . As with all groups described herein, the group may be unsubstituted or substituted. Substituted carbamoyl includes groups such as —CONY ² Y ^{3 where} Y ² and Y ³ are independently hydrogen, alkyl, cyano (lower alkyl), arylalkyl, heteroaralkyl, carboxy (lower alkyl), carboxy ( Aryl substituted lower alkyl), carboxy (carboxy substituted lower alkyl), carboxy (hydroxy substituted lower alkyl), carboxy (heteroaryl substituted lower alkyl), carbamoyl (lower alkyl), alkoxycarbonyl (lower alkyl) or alkoxycarbonyl (aryl substituted lower) Alkyl, provided that only one of Y ² and Y ³ can be hydrogen, and one of Y ² and Y ³ is carboxy (lower alkyl), carboxy (aryl-substituted lower alkyl), carbamoyl (lower alkyl) A If it is Koki aryloxycarbonyl (lower alkyl) or alkoxycarbonyl (aryl substituted lower alkyl), the other of Y ² and Y ³ and the like are hydrogen or alkyl. Preferred for Y ² and Y ³ are independently hydrogen, alkyl, cyano (lower alkyl), arylalkyl, heteroaralkyl, carboxy (lower alkyl), carboxy (aryl-substituted lower alkyl) and carbamoyl (lower alkyl). .

As used herein, N- (4-halo-3-methyl-5-isoxazolyl), N- (4-halo-5-methyl-3-isoxazolyl), N- (3,4- Dimethyl-5-isoxazolyl), N- (4-halo-5-methyl-3-isoxazolyl), N- (4-halo-3-methyl-5-isoxazolyl), N- (4,5-dimethyl-3- The isoxazolyl) derivative is the same as the compound in which Ar ² is specifically described above, but Ar ¹ is N- (4-halo-3-methyl-5-isoxazolyl), N- (4-halo-5). -Methyl-3-isoxazolyl), N- (3,4-dimethyl-5-isoxazolyl), N- (4-halo-5-methyl-3-isoxazolyl), N- (4-halo-3-methyl-5) -Isoxazolyl) Other is a N-(4,5-dimethyl-3-isoxazolyl), halo halide, preferably refers to compounds which are Cl or Br.

As used herein, abbreviations for protecting groups, amino acids and other compounds are IUPAC-IUB for general usage, generally accepted abbreviations or biochemical nomenclature for them, unless otherwise noted. It shall follow the Commission (IUPAC-IUB Commission on Biochemical Nomenclature; see (1972) Biochem ., 11: 942-944).

（ＩＩ） A. In the embodiments described in detail salt herein sulfonamide compounds, salts of the sulfonamide compounds used in the formulations and methods provided herein, preferably the sodium salt, Ar ¹ is at isoxazole Some are represented by Formula II below.

(II)

In the formula, R ¹ and R ² are any of the following (i), (ii) or (iii).
(I) R ¹ and R ² are each independently H, NH ₂ , NO ₂ , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, Haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amide, substituted or unsubstituted A substituted ureido; the alkyl, alkenyl, and alkynyl moieties have from 1 to about 14 carbon atoms and are either straight or branched or cyclic There, the aryl moiety is from about 4 to about 16 carbon atoms; provided that, ^{R 2} is not halide and pseudohalide; or (ii) ^{R 1} and ^{R 2} together form - a _{(CH 2) n} And n is 3-6; or (iii) R ¹ and R ² together form 1,3-butadienyl;

Provided that Ar ¹ is N- (5-isoxazolyl) or N- (3-isoxazolyl) (when the isoxazole is not 4-halo-isoxazole, 4-higher alkyl (C ₈ -C ₁₅ ) -isoxazole) If the compound is 4-biphenylsulfonamide substituted at the 2- or 6-position on the sulfonamide-bonded phenyl group, Ar ² is not phenyl or naphthyl.

In a preferred embodiment of the invention, R ¹ and R ² are each independently selected from alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, pseudohalide or H, provided that R ² is not a halide.

In certain embodiments, the sulfonamide is 4-chloro-3-methyl-5- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamide. ) isoxazole sodium ^salt; N 2 - (3- cyanomethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolyl Rusuru sulfamoyl) -2-thiophenecarboxamide Sodium salt; N ^2- (3-acetyloxymethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl) -2-thiophenecarboxamide sodium salt; and ^N 2 - (3- hydroxymethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-y It is selected on the condition that oxazolidone Rusuru sulfamoyl) not thiophenecarboxamide sodium salt.

In certain embodiments described in detail herein, Ar ² is 4-biphenyl or is a monocyclic heterocycle, particularly a 5-membered ring, or one or more, especially 1 A fused bicyclic or tricyclic heterocycle containing a heteroatom selected from S, O and NR ⁴² ; R ⁴² has about 30 or less carbon atoms, preferably 1-10, more preferably 1-6. And hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C (O) R ¹⁵ and S (O) _n R ¹⁵ (where n is 0) It is selected from a to 2 ^{a); R 15} is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl , Cycloalkenyl, cycloalkyl alkynyl; R ⁴² and R ¹⁵ is substituted with 1 or more substituents each independently selected from or Z is unsubstituted, Z is hydrogen, halide, pseudohalide, Alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C (O) R ¹⁶ , CO ₂ R ¹⁶ , SH, S (O) _n R ¹⁶ (n is 0 to 2), NHOH, NR ¹² R ¹⁶ , NO ₂ , N ₃ , OR ¹⁶ , R ¹² NCOR ¹⁶ and CONR ¹² R ¹⁶ ; R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl , Aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloal R ¹² is independently selected from R ⁴² and Z and is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C (O) R ¹⁷ and S (O) _n R ¹⁷ (n is 0-2); R ¹⁷ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, Cycloalkyl, cycloalkenyl or cycloalkynyl; each of R ⁴² , R ¹² , R ¹⁵ and R ¹⁶ may be further substituted by any of the groups described for Z.

In a preferred embodiment of the invention, R ⁴² is aryl such as phenyl or alkylphenyl, hydrogen or lower alkyl.

（ＩＩＩ） Therefore, in the compounds provided in the present invention, Ar ² includes thienyl, furyl and pyrrolyl, benzofuryl, benzopyrrolyl, benzothienyl, benzo [b] furyl, benzo [b] thienyl and indolyl (benzo [b] pyrrolyl) and 4-biphenyl and the like, and Ar ¹ is preferably N- (5-isoxazolyl) or N- (3-isoxazolyl). The sulfonamides are N-isoxazolyl sulfonamides, and the compound has the structure of the following formula III.

(III)

Wherein X is S, O or NR ¹¹ ; R ¹¹ is about 30 or less carbon atoms, preferably 1-10, more preferably 1-6, hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl , Heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C (O) R ¹⁵ and S (O) _n R ¹⁵ (n is 0-2); R ¹⁵ is hydrogen, Alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R ¹¹ and R ¹⁵ are unsubstituted or each independently selected from Z 1 Substituted with the above substituents, Z is hydrogen, halide, pseudohalide, alkyl, alkoxy Si, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C (O) R ¹⁶ , CO ₂ R ¹⁶ , SH, S (O) _n R ¹⁶ ( n is 0 to 2), NHOH, NR ¹² R ¹⁶ , NO ₂ , N ₃ , OR ¹⁶ , R ¹² NCOR ¹⁶ and CONR ¹² R ¹⁶ ; R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl , Alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R ¹² is independently selected from R ¹¹ and Z and is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle , Aralkyl, aralkoxy, cycloalkyl, Roarukeniru, cycloalkynyl, C ^{(O) R 17} and ^{_{S (O) n R 17 (}} n is 0-2)
Selected from;

R ¹⁷ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R ¹¹ , R ¹² , R ¹⁵ and R ¹⁶ are each Z R ¹¹ is preferably hydrogen, aryl such as phenyl or alkylphenyl, or lower alkyl; or the compound is preferably Ar ¹ , preferably N-, optionally substituted by any of the groups described for 4-biphenylsulfonamide which is (5-isoxazolyl) or N- (3-isoxazolyl).

In embodiments described in detail herein, Ar ² is a thienyl group, a furyl group, such as thienyl, furyl and pyrrolyl, or a benzo [b] derivative such as benzo [b] thienyl as described below, or A group that is a derivative or analog of a pyrrolyl group; Ar ¹ is N- (5-isoxazolyl) or N- (3-isoxazolyl). Ar ² has a structure of the following formula IV.

（ＩＶ）
式中、ＸはＯ、ＳまたはＮＲ^１１であり；Ｒ^１１は上記で定義した通りであり；

(IV)
Wherein X is O, S or NR ¹¹ ; R ¹¹ is as defined above;

The structure may be substituted at any or all positions, or an analogue of a group of formula (IV) in which the substituent forms a fused aromatic, aliphatic or heterocyclic ring, or R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the following (i) or (ii):
(I) R ⁸ , R ⁹ and R ¹⁰ each have hydrogen or about 50 or less, generally about 30 or less, more typically 20 or less carbons, each independently of hydrogen, halide, pseudo Halide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C (O) R ¹⁸ , (OAc) CH═CHR ¹⁸ , CO ₂ R ¹⁸ , SH, (CH ₂ ) _r C (O) (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH) _s (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r C ( ^{_{O) (CH = CH) s}} (CH 2) n R 18, (CH 2) r (CH = CH) s C (O) (CH 2) n R 18, (CH 2) r NH (CH = C ^{_{) S (CH 2) n R}} 18, C = N (OH) (CH 2) r R 18, (CH 2) r (CH = CH) s NH (CH 2) n R 18, (CH 2) r C _{^{(O) NH (CH 2)}} n R 18, C (O) (CH 2) r NH (CH 2) n R 18, (CH 2) r NH (CH 2) n R 18, (CH 2) r R ¹⁸ , S (O) _m R ¹⁸ (m is 0 to 2, s, n and r are each independently 0 to 6, preferably 0 to 3), HNOH, NR ¹⁸ R ¹⁹ , NO ₂ , Selected from N ₃ , OR ¹⁸ , R ¹⁹ NCOR ¹⁸ and CONR ¹⁹ R ¹⁸ ;

R ¹⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C (O) R ²⁰ and S (O) _n R ²⁰ (n is 0-2); R ¹⁸ and R ²⁰ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, Selected from aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; any of the groups described for R ⁸ , R ⁹ and R ¹⁰ is unsubstituted or substituted with a substituent described for Z, wherein Z is , Hydrogen, halide, pseudohalide, alkyl , Alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, _{^{cycloalkynyl, OH, CN, C (O}} ) R 21, CO 2 R 21, SH, S (O) _n R ²¹ (n is 0-2), NHOH, NR ²² R ²¹ , NO ₂ , N ₃ , OR ²¹ , R ²² NCOR ²¹ and CONR ²² R ²¹ ; R ²² is hydrogen, alkyl, alkenyl , Alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C (O) R ²³ and S (O) _n R ²³ where n is 0-2. Selected;

R ²¹ is independently selected from R ²³ , hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; provided that R ⁸ is NR ¹⁸ R ¹⁹ , OR ¹⁸ , R ¹⁹ NCOR ¹⁸ and CONR ¹⁹ R ¹⁸ COR ¹⁸ , (CH ₂ ) _r NH (CH═CH) _s (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH) _s NH (CH _{^{2) n R 18, (CH}} 2) r C (O) NH (CH 2) n R 18, C (O) (CH 2) r NH (CH 2) n R 18, (CH 2) r NH (CH _{2) n} R ¹⁸ or _{(CH 2)} a ^{r R 18,} when ^{R 18} is a 5-membered or 6-membered aryl group, the aryl group is 2 or more location Has a group, is preferably in position 2 one substituent is thienyl, with respect to connection between the furyl or pyrrolyl;

(Ii) any two of R ⁸ , R ⁹ and R ¹⁰ together with the carbon to which each is attached are about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members. A saturated or unsaturated aryl, aromatic, heteroaromatic, carbocyclic or heterocyclic ring; the ring is substituted by one or more substituents; each substituent is independently selected from Z The others of R ⁸ , R ⁹ and R ¹⁰ are selected as in (i); the heteroatom is NR ¹¹ , O or S; provided that Ar ² is 5-halo-3-lower alkyl Not benzo [b] thienyl, 5-halo-3-lower alkylbenzo [b] furyl, 5-halo-3-lower alkylbenzo [b] pyrrolyl.

  In embodiments provided herein, the alkyl, alkynyl, and alkenyl moieties of each listed substituent are straight or branched, acyclic or cyclic, preferably about 1 carbon atom. ~ 10. In more preferred embodiments, these moieties have 1 to 6 carbon atoms. Aryl, aliphatic, aromatic and heterocyclic groups can have 3 to 16, generally 3 to 7, more often 5 to 7 members in the ring and are single or fused rings be able to. The ring size and carbon chain length are such that the resulting molecule binds and retains activity as an endothelin antagonist or agonist, so that the resulting compound is at a concentration of less than about 100 μM. It is selected according to an amount that inhibits the binding of endothelin peptide to the endothelin receptor by 50% compared to the binding in the absence of sulfonamide.

In a preferred embodiment interesting in the present invention, R ⁹ and R ¹⁰ are hydrogen, halide or methyl, more preferably hydrogen or halide, and R ⁸ is CO ₂ R ¹⁸ , (CH ₂ ) _r C (O ) (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH) _s (CH ₂ ) _n R ¹⁸ , C═N (OH) (CH ₂ ) _r R ¹⁸ , (CH ₂ ) _r C (O ) (CH═CH) _s (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH) _s C (O) (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r NH (CH═CH) _{s ^{(CH 2) n R 18,}} (CH 2) r (CH = CH) s NH (CH 2) n R 18, (CH 2) r C (O) NH (CH 2) n R 18, C (O) (CH ₂ ) _r NH (CH ₂ ) _n R ¹⁸ , (CH _{2) r NH (CH 2)} n R 18, (CH 2) r from ^{R 18} is selected; however, ^{R 8} is _{^{CO 2 R 18, (CH 2}} ) r C (O) NH (CH 2) n R 18 , C (O) (CH ₂ ) _r NH (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r C (O) NH (CH ₂ ) _n R ¹⁸ or (CH ₂ ) _r R ¹⁸ , and R ¹⁸ is In the case of phenyl, the phenyl group is substituted at two or more positions, and preferably one or more of these substitution positions are ortho positions.

In preferred compounds, R ¹⁸ is aryl or heteroaryl, preferably having 5 or 6 ring atoms, more preferably phenyl or pyrimidinyl, and most preferably phenyl.

In the most preferred compounds of the invention, R ¹⁸ is phenyl, the group is substituted at multiple positions, most preferably one or more substituents are in the ortho position; R ⁹ and R ¹⁰ are each hydrogen , Halide or lower alkyl, preferably hydrogen; R ⁸ is C (O) NHR ¹⁸ , C (O) CH ₂ R ¹⁸ , (CH ₂ ) R ¹⁸ , provided that R ⁸ is C (O) NHR ^In the case of ¹⁸ , the phenyl group must have two or more substituents, preferably one of these substituents is in the ortho position.

In another preferred embodiment, Ar ² is benzo [b] thienyl, benzo [b] furyl or indolyl (benzo [b] pyrrolyl), provided that the benzene ring is substituted and the substituent is 5 halo, Other than 3-lower alkyl. Preferred substituents on the benzene ring include alkylenedioxy (especially methylenedioxy, preferably 3,4-methylenedioxy), ethylenedioxy, aryl (especially phenyl), dimethylamino, diethylamino, benzyl, alkoxy There are one or more selected from (especially lower alkoxy such as methoxy and ethoxy), halide and alkyl (preferably lower alkyl), but are not limited thereto.

In preferred compounds according to the invention, R ² is preferably selected from alkyl, lower alkenyl, lower alkynyl, lower haloalkyl or H; R ¹ is halide or lower alkyl, more preferably R ¹ is bromine or chlorine, methyl Or ethyl. In the most active compounds provided herein according to confirmation in an in vitro binding assay, R ¹ is bromine or chlorine. When used in vivo , R ¹ is preferably chlorine.

In the most preferred embodiment of the invention, the formulation contains a sodium salt of the above compound wherein R ⁸ is phenylacetyl. Of the compounds described herein, compounds that inhibit or enhance endothelin-mediated activity by about 50% at concentrations of less than about 10 μM are preferred. More preferably, a compound that inhibits or improves endothelin-mediated activity by about 50% at a concentration of less than about 1 μM, more preferably less than about 0.1 μM, more preferably less than about 0.01 μM, and most preferably less than about 0.001 μM. It is. Note that the IC ₅₀ concentration measured in the in vitro assay is a non-linear function of the incubation temperature, as described below. The preferred values quoted herein are for assays performed at 4 ° C. A slightly higher (see Table 1) IC ₅₀ concentration is observed when the assay is performed at 24 ° C. Therefore, the preferred IC ₅₀ concentration is about 10 times higher.

Further, the most preferred compound in terms of use in the methods provided in the present invention, there is ET _A selective compounds. That is, such compounds, as compared to the interaction between ET _B receptor at much lower concentrations (about 10-fold lower, preferably 100-fold lower in _{IC 50)} interact with ET _A receptors. In particular, less than about 10μM and ET _A, preferably less than 1 [mu] M, more preferably it interacts with _{an IC 50} of less than 0.1 [mu] M, compound interacts with _{an IC 50} of greater than about 10μM and ET _B, or ET _B with less than about 10 [mu] M, preferably below 1 [mu] M, more preferably it interacts with _{an IC 50} of less than 0.1 [mu] M, compounds that interact with _{an IC 50} of greater than about the ET _a 10 [mu] M is preferred.

Preferred compounds include compounds that bind compound is ET _B receptor selective or an IC ₅₀ of less than about 1μM to ET _B receptors are also included. ET _B selective compounds, as compared to the concentration that interact with ET _A receptors, which interact with ET _B receptors at least about 10 fold lower _{IC 50} concentrations. In such compounds, R ² is selected from alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide or H; R ¹ is halide or lower alkyl, and in a preferred embodiment R ¹ is bromine or chlorine, Preferably it is chlorine; R ⁹ and R ¹⁰ are independently selected from hydrogen, lower alkyl, preferably methyl or ethyl or halide, with a substituent at the 5-position (see, eg, Formulas III and IV) Certain R ⁸ are aryl or heterocyclic, especially phenyl and isoxazolyl, which are unsubstituted or substituted with Z, Z is preferably lower alkyl or halide.

1. When Ar ² is thiophene, pyrrole, furan, benzo [b] thiophene, indolyl (benzo [b] pyrrole) or benzo [b] furan, the sulfonamide salt provided by the present invention is represented by the following formula V There is a salt of the compound.

（Ｖ）
式中、Ｒ^１およびＲ^２は、以下の（ｉ）、（ｉｉ）または（ｉｉｉ）のいずれかである。
（ｉ）Ｒ^１およびＲ^２はそれぞれ独立に、Ｈ、ＮＨ_２、ＮＯ_２、ハライド、擬ハライド、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、ヘテロアリール、アルコキシ、アルキルアミノ、アルキルチオ、ハロアルコキシ、ハロアルキル、アルキルスルフィニル、アルキルスルホニル、アリールオキシ、アリールアミノ、アリールチオ、アリールスルフィニル、アリールスルホニル、アミノカルボニル、アリールアミノカルボニル、ハロアルキル、ハロアリール、アルコキシカルボニル、アルキルカルボニル、アリールカルボニル、ホルミル、置換もしくは未置換のアミド、置換もしくは未置換のウレイドから選択され；アルキル部分、アルケニル部分およびアルキニル部分は炭素原子数が１〜約１０である直鎖もしくは分岐鎖のいずれかであり、アリール部分は炭素原子数が約４〜約１４であり；ただし、Ｒ^２はハライド、擬ハライドおよび高級アルキルではなく；あるいは

(V)
In the formula, R ¹ and R ² are any of the following (i), (ii), or (iii).
(I) R ¹ and R ² are each independently H, NH ₂ , NO ₂ , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, Haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, aminocarbonyl, arylaminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amide Selected from substituted or unsubstituted ureido; the alkyl, alkenyl and alkynyl moieties may be linear or from 1 to about 10 carbon atoms Are either branched, the aryl moiety is from about 4 to about 14 carbon atoms; provided that, R ² is a halide, rather than a pseudo-halide and higher alkyl; or

(Ii) R ¹ and R ² are combined to form — (CH ₂ ) _n and n is 3 to 6; or (iii) R ¹ and R ² are combined to form 1, 3 -Forming butadienyl.

X is S, O or NR ¹¹ ; R ¹¹ has about 30 or less carbon atoms, preferably 1 to 10 and more preferably 1 to 6; hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, complex Selected from ring, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C (O) R ¹⁵ and S (O) _n R ^15, where n is 0-2; R ¹⁵ is hydrogen, alkyl, One or more alkenyl, alkynyl, aryl, alkylaryl, heterocyclic, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R ¹¹ and R ¹⁵ are unsubstituted or each independently selected from Z Substituted with a substituent, Z is hydrogen, halide, pseudohalide, alkyl, alkoxy, Alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C (O) R ¹⁶ , CO ₂ R ¹⁶ , SH, S (O) _n R ¹⁶ (n is 0 to 2), NHOH, NR ¹² R ¹⁶ , NO ₂ , N ₃ , OR ¹⁶ , R ¹² NCOR ¹⁶ and CONR ¹² R ¹⁶ ; R ¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkyl Aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R ¹² is independently selected from R ¹¹ and Z; hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl , Aralkoxy, cycloalkyl, cyclo Alkenyl selected from cycloalkynyl, C ^{(O) R 17} and ^{_{S (O) n R 17 (}} n is 0 to ^{2); R 17} is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle may R ^11, R ^12, respectively ^{R 15} and ^{R 16} are further substituted by any of the groups described for ^Z;; ring, aralkyl, aralkoxy, cycloalkyl alkyl, cycloalkenyl or cycloalkynyl ^{R 11} Is preferably hydrogen, aryl such as phenyl or alkylphenyl, lower alkyl;

R ⁸ , R ⁹ and R ¹⁰ each have hydrogen or no more than about 50, generally no more than about 30, more usually no more than 20 carbon atoms, each independently selected as described above. Preferably, it is selected from the following (i) or (ii).
(I) R ⁹ and R ¹⁰ are hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C (O) R ¹⁸ , (OAc) CH═CHR ¹⁸ , CO ₂ R ¹⁸ , SH, (CH ₂ ) _r C (O) (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH) _s (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r C (O) (CH═CH) _s (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH) _s C (O) (CH ₂ ) _{^{n R 18, (CH 2)}} r NH (CH = CH) s (CH 2) n R 18, C = n (OH) (CH 2) r R 18, (CH 2) r (CH = CH) s NH (CH _{^{) N R 18, (CH 2}} ) r C (O) NH (CH 2) n R 18, C (O) (CH 2) r NH (CH 2) n R 18, (CH 2) r NH (CH 2 ) _N R ¹⁸ , (CH ₂ ) _r R ¹⁸ , S (O) _m R ¹⁸ (m is 0 to 2, and s, n and r are each independently 0 to 6, preferably 0 to 3) , HNOH, NR ¹⁸ R ¹⁹ , NO ₂ , N ₃ , OR ¹⁸ , R ¹⁹ NCOR ¹⁸ and CONR ¹⁹ R ¹⁸ ; R ¹⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryl it is selected aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, from C ^{(O) R 20} and ^{_{S (O) n R 20 (}} n is 0-2) ; R ¹⁸ and R ²⁰ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocyclic, alkoxy, aryloxy, aralkyl, aralkoxy, selected from cycloalkyl, cycloalkenyl or cycloalkynyl;

R ⁸ is C (O) R ¹⁸ , (OAc) CH═CHR ¹⁸ , CO ₂ R ¹⁸ , (CH ₂ ) _r C (O) (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH ^{_{) s (CH 2) n R}} 18, (CH 2) r C (O) (CH = CH) s (CH 2) n R 18, (CH 2) r (CH = CH) s C (O) (CH _{^{2) n R 18, (CH}} 2) r NH (CH = CH) s (CH 2) n R 18, C = n (OH) (CH 2) r R 18, (CH 2) r (CH = CH) _s NH (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r C (O) NH (CH ₂ ) _n R ¹⁸ , C (O) (CH ₂ ) _r NH (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r NH (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r R ¹⁸ (m is 0 to 2, s, n and r are Each independently is 0-6, preferably 0-3, and R ¹⁸ is aryl, preferably phenyl; provided that R ⁸ is (CH ₂ ) _r C (O) NH (CH ₂ ) _n R ¹⁸ , C (O) (CH ₂ ) _r NH (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r NH (CH ₂ ) _n R ¹⁸ or (CH ₂ ) _r R ¹⁸ (especially r is And when R ¹⁸ is aryl, especially phenyl, R ¹⁸ must have at least two substituents, preferably at least one ortho substituent. Is;

Any of the groups described for R ⁸ , R ⁹ and R ¹⁰ are unsubstituted or substituted with the substituents described for Z, where Z is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, Alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C (O) R ²¹ , CO ₂ R ²¹ , SH, S (O) _n R ²¹ (n Are 0 to 2), NHOH, NR ²² R ²¹ , NO ₂ , N ₃ , OR ²¹ , R ²² NCOR ²¹ and CONR ²² R ²¹ ; R ²² is hydrogen, alkyl, alkenyl, alkynyl, aryl, Alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl R, cycloalkynyl, C (O) R ²³ and S (O) _n R ²³ (where n is 0 to 2); R ²¹ is independently R ²³ , hydrogen, alkyl, alkenyl, alkynyl, aryl Or selected from alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or

(Ii) any two of R ⁸ , R ⁹ and R ¹⁰ are about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members saturated or unsaturated aryl, aromatic Forming a ring, heteroaromatic ring, carbocycle or heterocycle; the ring is substituted by one or more substituents; each substituent is independently selected from Z; R ⁸ , R ⁹ and R The other of ¹⁰ is selected from the groups described for R ⁹ and R ¹⁰ in (i); the heteroatom is NR ¹¹ , O or S; provided that Ar ² is a 5-halo-3-lower alkylbenzo It is not [b] thienyl, 5-halo-3-lower alkylbenzo [b] furyl, 5-halo-3-lower alkylbenzo [b] pyrrolyl.

（ＩＶＡ） （ＩＶＢ） Thus, in these embodiments, Ar ² is represented by the following formulas (IVA and IVB).

(IVA) (IVB)

The structure may be substituted at any or all positions, or an analog of the group of formula (IV) in which the substituent forms a fused aromatic, aliphatic or heterocyclic ring. Yes; X is NR < ¹¹ >, O or S; R < ¹¹ > is hydrogen or up to about 30, preferably 1 to 10 and more preferably 1 to 6 carbon atoms, as defined above Selected as. R ⁸ , R ⁹ and R ¹⁰ are selected as described above.

In embodiments provided herein, when R ⁸ , R ⁹ and R ¹⁰ are selected as in (i), R ⁸ is preferably (CH ₂ ) _r C (O) (CH ₂ ). _{^{n R 18, (CH 2)}} r NH (CH 2) n R 18, (CH 2) r NH (CH 2) n R 18, (CH 2) r (CH = CH) s (CH 2) n R 18 (CH ₂ ) _r C (O) (CH═CH) _s (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH) _s C (O) (CH ₂ ) _n R ¹⁸ , (CH _{2 ) r (CH = CH) s} NH (CH 2) n R 18, C = n (OH) (CH 2) r R 18, (CH 2) r C (O) NH (CH 2) n R 18, C (O) (CH ₂ ) _r NH (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r NH (CH═CH) _s ( Selected from CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r C (O) NH (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r NH (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r R ¹⁸ ; However, ^{R 8} is _{(CH 2) r C (O} ) NH (CH 2) n R 18, be a (CH 2) r C (O ) NH (CH 2) n R 18 or _{(CH 2)} ^{r R 18} , R ¹⁸ is phenyl, the phenyl group is substituted at two or more positions, and preferably one or more of these positions are ortho positions.

In preferred of these compounds, R ¹⁸ is aryl or heteroaryl, preferably having 5 or 6 ring atoms, more preferably phenyl or pyrimidinyl, and most preferably phenyl. R ⁹ and R ¹⁰ are preferably hydrogen, halide, lower alkyl or halo lower alkyl.

More preferred compounds provided in the present invention are those in which the alkyl, alkynyl and alkenyl moieties are linear or branched, acyclic or cyclic and have from about 1 to about 10 carbon atoms. In some more preferred embodiments, these moieties have 1 to 6 carbon atoms and may be less than 6 carbon atoms. Aryl, allocyclic and heterocyclic groups can have 3 to 16, generally 3 to 7, more often 5 to 7 members in the ring and can be monocyclic or fused rings . The size of the ring and the length of the carbon chain is determined by the binding of the resulting molecule as an endothelin antagonist or agonist, as confirmed in in vitro or in vivo studies, particularly those exemplified herein. Is selected to show the activity of

In any of the above preferred embodiments, R ¹ and R ² are preferably independently selected from alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, pseudohalide, and H, provided that R ² is halide and It is not a pseudohalide, and in a preferred embodiment it is not a higher alkyl.

In a preferred embodiment, X is S, O, NR ¹¹ ; R ¹¹ is aryl, hydrogen or lower alkyl, preferably substituted or unsubstituted aryl (particularly preferably unsubstituted or lower alkyl or halogen). R ¹ is hydrogen, halide, pseudohalide, lower alkyl or lower haloalkyl, most preferably a halide; R ² is hydrogen, lower alkyl or lower haloalkyl. It is.

  Aryl groups are unsubstituted or substituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen, alkylenedioxy (especially methylenedioxy), amino, nitro and other such groups. The alkyl substituent is preferably lower alkyl, more preferably 1 to 3 carbon atoms.

In a more preferred embodiment, the two ^{R 9} and ^{R 10} is hydrogen, halide or lower alkyl, ^{R 8} is located at C (O) ^{NHR 18} or ^{_{C (O) CH 2 R 18}} ; R 18 is A phenyl group having at least two substitutions, most preferably one or more substituents at the ortho position, and further having a 3,4 or 4,5 alkylenedioxy substituent. In more preferred in these embodiments, X is S.

In all embodiments, R ¹ is preferably a halide, H, CH ₃ or C ₂ H ₅ ; R ² is H, CH ₃ , C ₂ H ₅ , C ₂ F ₅ or CF ₃ . In a further preferred embodiment, R ¹ is preferably Br, Cl or CH ₃ and R ² is H, CH ₃ , C ₂ H ₅ or CF ₃ .

In another embodiment, any two of R ⁸ , R ⁹ and R ¹⁰ form a ring so that Ar ² forms benzo [b] thienyl, benzo [b] furyl or benzo [b] pyrrolyl. Provided that there are one or more substituents, wherein the substituents are other than 5-halo and 3-lower alkyl; the other of R ⁸ , R ⁹ and R ¹⁰ are aryl, (CH _{2 ^{) r R 18, C (O}} ) R 18, CO 2 R 18, NR 18 R 19, SH, is ^{_{S (O) n R 18 (}} n is _{0~2), HNOH, NO 2,} n 3, OR ¹⁸ , R ¹⁹ selected from NCOR ¹⁸ and CONR ¹⁸ R ¹⁹ . Ar ² may be further substituted with any of the groups described for R ⁸ , R ⁹ and R ¹⁰ , preferably alkyl, alkoxy, alkoxyalkyl, aryl, alkylaryl, aminoalkyl, arylamino, aryl Selected from substituted amino and NR ¹¹ .

In embodiments where an ET _B antagonist is desired, R ⁸ and R ¹⁰ are hydrogen or lower alkyl, and R ⁹ preferably comprises a 3-14 membered, more preferably 5-7 membered heterocyclic or aromatic ring. . Specifically, when X is S, R ⁸ and R ¹⁰ are H or lower alkyl, and R ⁹ includes an aryl group, particularly a substituted phenyl such as a 2-lower alkyl substituent. The aryl moiety is substituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen, alkylenedioxy (especially methylenedioxy), amino, nitro and other such groups. The alkyl substituent is preferably lower alkyl, more preferably 1 to 3 carbon atoms.

When X is NR ¹¹ , R ¹¹ is aryl, in particular unsubstituted phenyl or substituted phenyl such as isopropylphenyl.

Other preferred compounds are ET _B activity, Ar ² has the structure of Formula IVB, R ⁹ is aryl or Z-substituted aryl, particularly phenyl, is a compound Z is lower alkyl or lower alkoxy.

In all embodiments of all compounds in the present invention, R ¹ is preferably a halide or lower alkyl, most preferably Br, and the compound is 2- or 3-sulfonamide with reference to Formula IV , Especially thiophenesulfonamides. In certain embodiments provided herein, Ar ² is a benzo [b] thienyl, benzo [b] furyl or indolyl (benzo [b] pyrrolyl) group, and the compounds provided in the present invention are preferably Are benzo [b] thienyl-, benzo [b] furyl- or indolylsulfonamides. Preferred compounds in the present invention include benzo [b] thienyl, benzo [b] furyl and indolyl 2- or 3-sulfonamides. In the benzo [b] thienyl, benzo [b] furyl and indolyl 2- or 3-sulfonamides provided in the present invention, the benzene group has one or more substituents, and the substituents are 5-halo and 3- It is selected on the condition that it is other than lower alkyl.

Particularly interesting compounds are salts of compounds of the formula III, in particular sodium salts, wherein Ar ² is a phenyl-, benzothienyl, benzofuryl or indolyl [benzopyrrolyl] group, or Ar ² is a substituent having two or more substituents Substituted phenylaminocarbonylthienyl, substituted phenylaminocarbonylfuryl, substituted aminocarbonylpyrrolyl group, or Ar ² is phenylacetylthienyl, phenylacetylfuryl or phenylacetylpyrrolyl or acetoxystyrylthienyl, acetoxystyryl Examples include salts that are furyl or acetoxystyrylpyrrolyl groups.

The most preferred compounds provided herein, in exemplary assays herein, when measured at 4 ° C. Following the procedure described in Example, IC ₅₀ of less than 0.1μM for ET _A receptors, more preferably A salt of a compound that is less than 0.01 μM, more preferably less than 0.001 μM (see, eg, Table 1 for representative experimental results). When measured at 24 ° C., the IC ₅₀ concentration is slightly higher (2-10 times; see Table 1 for some comparative values).

（ＶＩ）
式中、Ｍは（ＣＨ_２）_ｍＣ（Ｏ）（ＣＨ_２）_ｒ、（ＣＨ_２）_ｍＣ（Ｏ）ＮＨ（ＣＨ_２）_ｒ、（ＣＨ_２）_ｍ（ＣＨ＝ＣＨ）（ＣＨ_２）_ｒ、（ＣＨ_２）_ｍＣ（Ｏ）（ＣＨ_２）_ｓＮＨ（ＣＨ_２）_ｒ、（ＣＨ_２）_ｍ（ＣＨ＝ＣＨ）（ＣＨ_２）_ｒ、Ｃ＝Ｎ（ＯＨ）（ＣＨ_２）_ｒ、（ＣＨ_２）_ｍＣ（Ｏ）（ＣＨ＝ＣＨ）_ｓＮＨ（ＣＨ_２）_ｒ、ＣＨ（ＯＨ）（ＣＨ_２）_ｒ、ＣＨ（ＣＨ_３）Ｃ（Ｏ）（ＣＨ_２）_ｒ、ＣＨ（ＣＨ_３）Ｃ（Ｏ）（ＣＨ_２）_ｍ（ＣＨ＝ＣＨ）（ＣＨ_２）_ｒ、（ＣＨ_２）_ｒ、（ＣＨ_２）_ｒＯ、Ｃ（Ｏ）Ｏ（ｍ、ｓおよびｒはそれぞれ独立に、０〜６、好ましくは０〜３である）であり；より好ましくはＭは、（ＣＨ_２）_ｍＣ（Ｏ）（ＣＨ_２）_ｒ、（ＣＨ_２）_ｍＣ（Ｏ）ＮＨ（ＣＨ_２）_ｒ、（ＣＨ_２）_ｍ（ＣＨ＝ＣＨ）（ＣＨ_２）_ｒ、（ＣＨ_２）_ｍＣ（Ｏ）（ＣＨ_２）_ｓＮＨ（ＣＨ_２）_ｒ、（ＣＨ_２）_ｍ（ＣＨ＝ＣＨ）（ＣＨ_２）_ｒ、Ｃ＝Ｎ（ＯＨ）（ＣＨ_２）_ｒ、ＣＨ（ＯＨ）（ＣＨ_２）_ｒ、（ＣＨ_２）_ｒ、（ＣＨ_２）_ｒＯ、Ｃ（Ｏ）Ｏであり；
Ｒ^３１、Ｒ^３２、Ｒ^３３、Ｒ^３４およびＲ^３５は、それぞれ独立に、以下の（ｉ）または（ｉｉ）から選択され Among the preferred compounds of interest in the present invention are salts wherein Ar ² has the structure of formula VI

(VI)
In the formula, M represents (CH ₂ ) _m C (O) (CH ₂ ) _r , (CH ₂ ) _m C (O) NH (CH ₂ ) _r , (CH ₂ ) _m (CH═CH) (CH ₂ ). _{r, (CH 2) m C} (O) (CH 2) s NH (CH 2) r, (CH 2) m (CH = CH) (CH 2) r, C = N (OH) (CH 2) r , (CH ₂ ) _m C (O) (CH═CH) _s NH (CH ₂ ) _r , CH (OH) (CH ₂ ) _r , CH (CH ₃ ) C (O) (CH ₂ ) _r , CH ( CH ₃ ) C (O) (CH ₂ ) _m (CH═CH) (CH ₂ ) _r , (CH ₂ ) _r , (CH ₂ ) _r O, C (O) O (m, s and r are independent of each other. to 0-6, preferably be a a) 0-3; more preferably M _{is, (CH 2) m C (} O) (CH 2) r, (CH 2) m C _{O) NH (CH 2) r} , (CH 2) m (CH = CH) (CH 2) r, (CH 2) m C (O) (CH 2) s NH (CH 2) r, (CH 2) _{m (CH = CH) (CH} 2) r, C = N (OH) (CH 2) r, CH (OH) (CH 2) r, (CH 2) r, (CH 2) r O, C (O ) O;
R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are each independently selected from the following (i) or (ii)

(I) R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are each independently H, OH, NHR ³⁸ , CONR ³⁸ R ³⁹ , NO ₂ , cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, Aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl Alkylaminocarbonyl, aminocarbonyl, (alkylaminocarbonyl) alkyl, carboxy, carboxyalkyl, carboxyalkenyl, alkyls Selected from sulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkoxyalkoxy, hydroxyalkyl, (acetoxy) alkoxy, (hydroxy) alkoxy and formyl; or

(Ii) two or more of R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ in which adjacent ring carbons are substituted are combined to form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy _{(i.e., -O- (CH 2) n -O} -, - S- (CH 2) n -O -, - S- (CH 2) n -S-; n 1-4 is preferably 1 or 2 The group is unsubstituted or substituted by replacing one or more hydrogens with a halide, lower alkyl, lower alkoxy or halolower alkyl; R ³¹ , R ³² , The others of R ³³ , R ³⁴ and R ³⁵ are selected as in (i);

R ³⁸ and R ³⁹ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl. Preferably hydrogen, lower alkyl, lower alkoxy and lower haloalkyl; provided that when M is (CH ₂ ) _m C (O) NH (CH ₂ ) _r , R ³¹ , R ³² , R ³³ , R ³⁴ And two or more of R ³⁵ are not hydrogen.
M is most preferably selected from:

In general, however, regardless of the choice of M, Ar ² has the structure of formula V or VI, or in all those compounds where R ⁸ contains an aryl group, the aryl substituent has one or more substituents, Or it is preferable to have one or more substituents in the ortho position. Preferably, aryl is preferably in the ortho position, more preferably in one or more other positions, in particular in the 4 and 6 positions, or when the substituents are linked together to form alkylenedioxy (or one or both oxygens). An analog substituted with S) is a phenyl substituted at an adjacent position such as 3, 4 or 4,5.
In all compounds, at least one of R ³¹ and R ³⁵ is other than hydrogen.

In more preferred _{compounds, M} is _{C (O) CH 2, C} (O) NH, -CH = CH-, CH 2 CH 2 C (O) (CH) 2, CH 2 CHC (O) CH 2, Most preferably, it has the structure of the following formula VII.

（ＶＩＩ）
式中、ＷはＣＨ_２またはＮＨである。
Ｍはさらに好ましくは、以下のものから選択される。

(VII)
In the formula, W is CH ₂ or NH.
M is more preferably selected from:

In the formula, R ⁴⁰ is preferably hydrogen, alkyl, alkoxy, alkoxyalkyl, haloalkyl, more preferably lower alkyl, lower alkoxy or halolower alkyl, more preferably hydrogen or lower alkyl, especially Methyl or ethyl, most preferably hydrogen.
M is most preferably

In preferred compounds, R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are selected from the following (i) or (ii):
(I) R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are each independently lower alkyl, halo lower alkyl, phenyl, alkoxy, lower alkylsulfonylamino lower alkyl, cyano lower alkyl, acetyl, lower alkoxycarbonyl, Selected from cyano, OH, acetoxy lower alkyl, hydroxy lower alkyl, acetoxy lower alkoxy or lower alkoxycarbonyl; or (ii) R ³² and R ³³ or R ³³ and R ³⁴ are alkylenedioxy, preferably methylenedioxy Other than R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are selected as in (i).

In a preferred embodiment, R ³¹ , R ³³ and R ³⁵ are other than hydrogen, preferably lower alkyl or lower alkoxy, or R ³¹ or R ³⁵ is other than hydrogen, preferably lower alkyl or lower alkoxy. R ³² and R ³³ or R ³³ and R ³⁴ form methylenedioxy.

  In any embodiment, preferred substituents can be determined with reference to Table 1 showing exemplary compounds. Preferred compounds are those of Table 1 with the highest activity, and preferred substituents are those on the compound with the highest activity.

^＊結果は２〜５回の実験の平均である。
^＊＊予備的結果または１以上のデータ点が近似的に決定されている結果。 Table 1

^* Results are the average of 2-5 experiments.
^** Preliminary results or results where one or more data points are approximately determined.

^† Assay performed with incubation at 24 ° C. As described in the Examples, this relatively high temperature incubation reduces the activity by about 1/2 to about 1/10 compared to the activity at 4 ° C.
^- : Data not obtained or measured as% inhibition at 100 μM.
%:% Inhibition at 100 μM.

The 4-bromo or 4-chloro group can be replaced by other 4-halo substituents or other suitable substituents for R ¹ , such as alkyl, in particular alkyl having about 1 to 15 carbon atoms in the chain. Is clear.

2. When Ar ² is a substituted 4-biphenyl group , compounds of formula I are provided wherein Ar ¹ is N- (5-isoxazolyl) or N- (3-isoxazolyl and Ar ² is selected from biphenyl derivatives. The compound can be represented by the following formula (VII).

式中、Ｒ^２６およびＲ^１３はそれぞれ独立に、Ｈ、ＯＨ、ＨＯＮＨ、ＮＨ_２、ＮＯ_２、ハライド、擬ハライド、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、ヘテロアリール、アルコキシ、アルキルアミノ、ジアルキルアミノ、アルキルチオ、ハロアルコキシ、ハロアルキル、アルキルスルフィニル、アルキルスルホニル、アリールオキシ、アリールアミノ、アリールチオ、アリールスルフィニル、アリールスルホニル、ハロアルキル、ハロアリール、アルコキシカルボニル、カルボニル、アルキルカルボニル、アミノカルボニル、アリールカルボニル、ホルミル、置換もしくは未置換のアミド、置換もしくは未置換のウレイドであり；アルキル部分、アルケニル部分およびアルキニル部分は炭素原子数が１〜約１４、好ましくは１〜６であって、直鎖もしくは分岐鎖または環状のいずれかであり、アリール部分は炭素原子数が約４〜約１６、好ましくは４〜１０である。Ｒ^２６およびＲ^１３は好ましくは、それぞれＨ、低級アルキル、ハロアルキルおよびハライドから選択される。やはり、Ａｒ^２は２個以上の置換基で置換されていても良く、該置換基はそれぞれ独立に、Ｒ^２６およびＲ^１３について記載した選択肢から選択され、Ｒ^２およびＲ^１は上記で定義した通りであることは明らかである。

Wherein R ²⁶ and R ¹³ are each independently H, OH, HONH, NH ₂ , NO ₂ , halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, dialkyl Amino, alkylthio, haloalkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted Or an unsubstituted amide, a substituted or unsubstituted ureido; the alkyl, alkenyl and alkynyl moieties have from 1 to about 1 carbon atom , Preferably a 1-6 are either straight or branched chain or cyclic, aryl moiety is from about 4 to about carbon atoms 16, preferably 4 to 10. R ²⁶ and R ¹³ are preferably selected from H, lower alkyl, haloalkyl and halide, respectively. Again, Ar ² may be substituted with two or more substituents, each substituent being independently selected from the options described for R ²⁶ and R ¹³ , where R ² and R ¹ are as defined above Obviously it is.

In embodiments of the present invention, there biphenyl sulfonamides substituted 4-biphenyl sulfonamides; R ¹³ is preferably in the para position; R ^26, if not hydrogen, is in the position other than the 2-position.

In a more preferred embodiment, R ¹ is halide or methyl or higher (C ₉ -C ₁₃ ) alkyl. R ¹ is a _halide, a _{CH 3, C 2 H 5,} CF 3, C 2 F 5, n-C 3 H 7 and cyclo _-C 3 _{H 7,} preferably be a halide or CH _3; ^{R 2} is is selected from _{H, CH 3, C 2 H 5,} CF 3, C 2 F 5, n-C 3 H 7 and cyclo _-C 3 _{H 7,} more preferably ^{R 1} is halide or CH _3, ^{R 2} Is selected from H, CH ₃ , C ₂ H ₅ or CF ₃ .

In a more preferred embodiment, R ¹ is Cl or Br, or higher alkyl (C ₉ H _{19 to} C ₁₃ H ₂₇ ) if higher ETB activity is preferred; R ² is H, CH ₃ , C ₂ H ₅ , CF ₃ , C ₂ F ₅ , n-C ₃ H ₇ , cyclo-C ₃ H ₇ , nC ₁₃ H ₂₇ and nC ₉ H ₁₉ . In a more preferred embodiment, R ¹ is Cl, Br or C ₉ H ₁₉ -C ₁₃ H ₂₇ ; R ² is H, CH ₃ , C ₂ H ₅ or CF ₃ .

Biphenyl compounds provided in the present invention are ET _A selective or ET _B selective (e.g. see Table 2). That is, the compounds provided herein, as compared to the inhibition of binding of endothelin to ET _A receptors at a concentration of about 1/10 to 1/30, the binding of endothelin to ET _B receptors Inhibit. In particular, 4-biphenyl sulfonamides are ET _B selective.

In all embodiments of the present invention, 4-halo benzisoxazolyl sulfonamides, as shown herein, when evaluated in an assay that measures binding to ET _A and / or ET _B receptors , Which exhibits a considerably higher activity for at least one of the ET receptors compared to the corresponding sulfonamides in which the 4-position substituent in the isoxazolyl is other than a halogen such as alkyl (approximately 2 to 20 times the activity) ). For example, whereas the _{IC 50} of approximately 0.008μM for ET _A receptors N-(3,4-dimethyl-5-isoxazolyl) -2-biphenyl sulfonamide, N-(4-bromo-3- The IC ₅₀ of methyl-5-isoxazolyl) -2-biphenylsulfonamide is about 0.016 μM (see Table 2 below). And (3) N- (3,4- dimethyl-5-isoxazolyl) -3- whereas _{IC 50} of approximately 3.48μM against ET _B receptors biphenyl sulfonamide, N-(4-bromo - 3-methyl-5-isoxazolyl) _{-3-IC 50} for ET _B receptors biphenyl sulfonamide is approximately 0.76μM, N- (4- chloro-3 methyl-5-isoxazolyl) -3-biphenylsulfonamide _{IC 50} for ET _B receptors amide is about 0.793MyuM (see Table 2 below).

  Examples of biphenylsulfonamides include the following and those shown in Table 2, N- (3-methyl-5-isoxazolyl) -4′-methylphenyl-4-biphenylsulfonamide, N- (4 -Bromo-3-methyl-5-isoxazolyl) -4'-methylphenyl-4-biphenylsulfonamide, N- (4-chloro-3-methyl-5-isoxazolyl) -4'-methylphenyl-4-biphenylsulfone Amide, (3-Methyl-5-isoxazolyl) -4′-trifluoromethylphenyl-4-biphenylsulfonamide, (4-Bromo-3-methyl-5-isoxazolyl) -4′-trifluoromethylphenyl-4- Biphenylsulfonamide, (3-methyl-5-isoxazolyl) -4′-methoxyphenyl-4 Biphenylsulfonamide, (4-bromo-3-methyl-5-isoxazolyl) -4'-methoxyphenyl-4-biphenylsulfonamide, (4-bromo-3-methyl-5-isoxazolyl) -3'-methoxyphenyl- 4-biphenylsulfonamide, (4-bromo-3-methyl-5-isoxazolyl) -2'-methoxyphenyl-4-biphenylsulfonamide, N- (4-bromo-3-methyl-5-isoxazolyl) -3 ' , 4'-methylenedioxyphenyl-4-biphenylsulfonamide and (4-bromo-3-methyl-5-isoxazolyl) -3'-methylphenyl-4-biphenylsulfonamide, but are not limited thereto. It is not a thing. Corresponding 4-chloro and 4-fluoroisoxazolyl compounds are also included in the present invention.

  When an assay (see Examples) exemplifying specific biphenyl compounds was examined, the results are as shown in the following table (Table 2). However, the results are given by way of example or provided for comparison with the compounds provided herein and are not intended to limit the present invention.

^＊同一の製造品についての１回、２回または３回の実験からの結果。
^＊＊予備的結果。 Table 2

^* Results from one, two or three experiments on the same product.
^** Preliminary results.

Preferred compounds are those in which Ar ² is 4-biphenyl with respect to formula VII and one or more substituents R ¹³ are in the para position. Preferred substituents are lower alkyl, halo lower alkyl and lower alkoxy. Such compounds are ET _B activity.

  The preparation of the compounds having the above and other necessary activities is given in the examples.

式中、Ａｒ^１はイソオキサゾリルであり、Ａｒ^２は下記式の構造を有する。 B. Sulfonamides and sulfonamide derivatives Sulfonamides and sulfonamide derivatives are also provided. These compounds are active in assays that measure endothelin antagonist activity. The sulfonamide has a structure represented by the following formula.

In the formula, Ar ¹ is isoxazolyl, and Ar ² has a structure represented by the following formula.

Where R ³ and R ⁴ are hydrogens or substituents that are believed to increase the tolerability of the compound (ie, by changing the pharmacokinetic aspects of the compound). Such substituents are preferably independently selected from halo, cyano, cyanoalkyl, C (O) R ⁴¹ , alkyl, alkenyl, cycloalkyl and aryl, or R ³ and R ⁴ together. Forming an alkylene; W is O, NH or CH ₂ ;
R ⁵ , R ⁶ and R ⁷ are each independently selected as in (i) or (ii) below;

(I) R ⁶ is hydrogen, unsubstituted alkyl, hydroxyl, unsubstituted alkoxy, C (O) R ⁴¹ , carbamoyloxy or alkoxycarbonyloxy;
R ⁵ and R ⁷ are each independently selected from hydrogen, unsubstituted alkyl, hydroxyl, C (O) R ⁴¹ , carbamoyloxy and alkoxycarbonyloxy; or

(Ii) when at least one of R ³ and R ⁴ is not hydrogen, any two can form alkylenedioxy, the others are selected as in (i);
R ⁴⁵ is alkyl, C (O) R ⁴¹ , (CH ₂ ) _x OH and CH (OH) (CH ₂ ) _x CH ₃ (x is 0 to 6), S (O) _n R ⁴¹ (n It is selected from a a) and ^{C (= NR 43) R 41} 0~2;
R ⁴¹ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, (aryl) (alkyl) amino, alkylsulfonylamino, arylsulfonylamino, (alkylsulfonyl) ) (Alkyl or aryl) amino or (arylsulfonyl) (alkyl or aryl) amino; R ⁴³ is selected from hydroxyl, alkoxy, alkyl and aryl. R ⁴¹ and R ⁴³ are unsubstituted or substituted with one or more substituents selected from Y; Y is alkoxy, halide, pseudohalide, alkylcarbonyl, arylcarbonyl, amino, alkylamino, Defined as dialkylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl or hydroxyl group. Furthermore, the corresponding 3-acyl-2-thiophenesulfonamides are also interesting.

These compounds show superior efficacy, potency, bioavailability, in vivo half-life and / or stability compared to compounds with aryl groups having more than two hydrogen substituents. There appears to be no toxic effects related to hydrophobicity (see Table 4). In addition, these compounds appear to give good results in standard in vitro toxicity studies.

For in vivo administration, it has been found desirable to have a suitable degree of hydrophilicity that reduces the hemolytic properties of the compound. For example, in the present invention it is recognized that it is obtained when the aryl group is tetra-substituted, penta-substituted or hexa-substituted, preferably penta-substituted. When the aryl group is tetra-substituted, it is preferably substituted at the 2-position, 4-position and 6-position, and one of these substituents is a polar group such as a hydroxyl group, acetoxy, carboxy and carboxamide. Such substitution increases the endothelin antagonist activity and hydrophilicity of the compound. When the aryl group is substituted at the 2-position, 4-position and 6-position by a nonpolar group such as an alkyl group (more specifically, a methyl group), the aryl group is preferably penta-substituted or hexa-substituted. In the penta-substituted aryl group, the fifth substituent is at the 3-position, and is preferably a polar group such as a hydroxyl group, acetoxy, carboxy and carboxamide. Such substitution is preferred for obtaining very high levels of activity for therapy.

Such substitutions give the compounds good bioavailability, long in vivo half-life and / or good in vivo efficacy. In view of the disclosure herein, other such optimal substituent patterns and substituents can be determined empirically using suitable animal models.

As noted above, the compounds of this embodiment provide higher tolerability compared to similar compounds known in the art. Such high tolerance is caused by changes in the pharmacokinetic aspects of the compound. Pharmacokinetic aspects were based on many factors including but not limited to bioavailability, in vivo half-life, in vivo potency, efficacy, stability, receptor selectivity Is.

In certain embodiments, the compound is wherein no more than one of R ⁵ , R ^6, and R ⁷ is hydrogen and the compound is N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfonamide, N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl) phenylacetyl-3 -Thiophenesulfonamide, N- (3,4-dimethyl-5-isoxazolyl) -2-[(2,4,6-trimethylphenoxy) carbonyl] thiophene-3-sulfonamide, N- (4-chloro-3- Methyl-5-isoxazolyl) -2-[(2,4,6-trimethylphenoxy) carbonyl] thiophene-3-sulfonamide and N- (4-bromo-3- It is selected on the condition that it is not methyl-5-isoxazolyl) -2-[(2,4,6-trimethylphenoxy) carbonyl] thiophene-3-sulfonamide.

  In another embodiment, the sulfonamide further comprises wherein the compound is N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-methoxy-2,4,6-trimethylphenylaminocarbonyl) thiophene- 3-sulfonamide, N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-hydroxy-2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfonamide, N- (4 -Chloro-5-methyl-3-isoxazolyl) -2- (3-hydroxy-2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfonamide and N- (3,4-dimethyl-5-isoxazolyl) -2- (3-hydroxy-2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfone It is selected under the condition that it is not in degrees.

In preferred compounds, R ³ and R ⁴ are each independently hydrogen, alkyl, halo, cyano, cyanomethyl, acetyl or cycloalkyl, or together form an alkylene;
R ⁵ , R ⁶ and R ⁷ are each independently selected as in (i) or (ii) below (provided that no more than one of R ⁵ , R ⁶ and R ⁷ is hydrogen);
(I) R ⁶ is hydrogen, unsubstituted alkyl, hydroxyl, unsubstituted alkoxy, C (O) R ⁴¹ , carbamoyloxy or alkoxycarbonyloxy,
R ⁵ and R ⁷ are each independently hydrogen, unsubstituted alkyl, hydroxyl, C (O) R ⁴¹ , carbamoyloxy or alkoxycarbonyloxy; or

(Ii) if at least one of R ³ and R ⁴ is not hydrogen, any two can form alkylenedioxy, the other is selected as described in (i);
x is 0 or 1; n is 2; R ⁴¹ is alkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino or arylsulfonylamino; ^R43 is a hydroxyl group Or there are compounds selected from alkoxy. However, this compound is N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfonamide, N- (4-chloro- 3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl) phenylacetyl-3-thiophenesulfonamide, N- (3,4-dimethyl-5-isoxazolyl) -2-[(2,4 , 6-Trimethylphenoxy) carbonyl] thiophene-3-sulfonamide, N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(2,4,6-trimethylphenoxy) carbonyl] thiophene-3- Sulfonamide and N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(2,4,6-trimethylphenoxy) Carbonyl] not thiophen-3-sulfonamide.

Particularly preferred compounds are those where Ar ¹ is 4-chloro-3-methyl-5-isoxazolyl; R ³ and R ⁴ are each independently hydrogen, methyl, cyclopropyl, fluorine, chlorine, cyano, cyanomethyl or acetyl. Is or together forms butylene;
R ⁵ , R ⁶ and R ⁷ are each independently selected from the following (i) or (ii) (provided that no more than one of R ⁵ , R ⁶ and R ⁷ is hydrogen);
(I) R ⁶ is hydrogen, methyl, hydroxyl group, methoxy, acetyl, carbamoyloxy or methoxycarbonyloxy,
R ⁵ and R ⁷ are each independently hydrogen, methyl, hydroxyl, acetyl, carbamoyloxy and methoxycarbonyloxy; or

(Ii) when at least one of R ³ and R ⁴ is not hydrogen, R ⁶ and R ⁷ can form methylenedioxy and R ⁵ is selected as described in (i);
R ⁴⁵ is acetyl, propanoyl, 2-methylpropanoyl, cyclopropylcarbonyl, benzoyl, cyclohexylcarbonyl, methyl, 1-hydroxy-1-ethyl, hydroxymethyl, methoxyacetyl, fluoroacetyl, carboxyacetyl, hydroxyacetyl, oxyimino A compound that is acetyl or SO ₂ R ⁴¹ . However, this compound is N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethylphenylaminocarbonyl) thiophene-3-sulfonamide, N- (4-chloro- 3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl) phenylacetyl-3-thiophenesulfonamide, N- (3,4-dimethyl-5-isoxazolyl) -2-[(2,4 , 6-Trimethylphenoxy) carbonyl] thiophene-3-sulfonamide, N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(2,4,6-trimethylphenoxy) carbonyl] thiophene-3- Sulfonamide and N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(2,4,6-trimethylphenoxy) Carbonyl] not thiophen-3-sulfonamide.

Particularly preferred compounds are selected from:
N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide;
N- (2-benzoyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-hydroxyethaneimidoyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide;

3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-propionylphenyl) -2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-isobutyryl-4,6-dimethylphenyl) -2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclohexylcarbonyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclopropylcarbonyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide;

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thienyl) carbonyl) amino) -2,4,6-trimethylphenylcarbamate;
3-(((3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thienyl) carbonyl) amino) -2,4,6-trimethylphenylmethyl carbonate;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-methoxy-2,4,6-trimethylphenyl) acetyl) -3-thiophenesulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-hydroxy-2,4,6-trimethylphenyl) acetyl) -3-thiophenesulfonamide;

3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-hydroxy-1-methylethyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide ;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-hydroxyethyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2,6-diacetyl) -4-methylphenyl) -2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-methoxyacetyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide;
3- (2-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thienyl) carbonyl) amino) -3,5-dimethylphenyl) -3-oxopropanoic acid;

3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-glycidyl-4,6-dimethylphenyl) -2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-methylsulfonyl) phenyl) -2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-((methylamino) sulfonyl) phenyl) -2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-((dimethylamino) sulfonyl) phenyl) -2-thiophenecarboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-(((methylsulfonyl) amino) carbonyl) phenyl) -2-thiophenecarboxamide ;

3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-fluoroacetyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide;
N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-methyl-2-thiophenecarboxamide;
N- (2-benzoyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-methyl-2-thiophenecarboxamide;

3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-hydroxyethaneimidoyl) -4,6-dimethylphenyl) -5-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-propionylphenyl) -5-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-isobutyryl-4,6-dimethylphenyl) -5-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclohexylcarbonyl) -4,6-dimethylphenyl) -5-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclopropylcarbonyl) -4,6-dimethylphenyl) -5-methyl-2-thiophenecarboxamide;

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- (5-methylthienyl) carbonyl) amino) -2,4,6-trimethylphenylcarbamate;
3-(((3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- (5-methylthienyl) carbonyl) amino) -2,4,6-trimethylphenylmethyl carbonate ;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-methoxy-2,4,6-trimethylphenyl) acetyl) -5-methyl-3-thiophenesulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-hydroxy-2,4,6-trimethylphenyl) acetyl) -5-methyl-3-thiophenesulfonamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-hydroxy-1-methylethyl) -4,6-dimethylphenyl) -5-methyl- 2-thiophenecarboxamide;

3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-hydroxy-1-ethyl) -4,6-dimethylphenyl) -5-methyl-2 -Thiophene carboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2,6-diacetyl) -4-methylphenyl) -5-methyl-2-thiophenecarboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-methoxyacetyl) -4,6-dimethylphenyl) -5-methyl-2-thiophenecarboxamide ;
3- (2-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- (5-methylthienyl)) carbonyl) amino) -3,5-dimethylphenyl) -3-oxo Propanoic acid;

3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-glycolyl-4,6-dimethylphenyl) -5-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-methylsulfonyl) phenyl) -5-methyl-2-thiophenecarboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-((methylamino) sulfonyl) phenyl) -5-methyl-2-thiophene Carboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-((dimethylamino) sulfonyl) phenyl) -5-methyl-2-thiophene Carboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-((methylsulfonyl) amino) carbonyl) phenyl) -5-methyl-2 -Thiophene carboxamide;

3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-fluoroacetyl) -4,6-dimethylphenyl) -5-methyl-2-thiophenecarboxamide ;
N- (6-acetyl-4-methyl-1,3-benzodioxol-5-yl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-methyl -2-thiophenecarboxamide;
N- (4-acetyl-6-methyl-1,3-benzodioxol-5-yl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-methyl -2-thiophenecarboxamide;
N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -4-methyl-2-thiophenecarboxamide;
N- (2-benzoyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -4-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-hydroxyethaneimidoyl) -4,6-dimethylphenyl) -4-methyl-2-thiophenecarboxamide;

3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-propionylphenyl) -4-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-isobutyryl-4,6-dimethylphenyl) -4-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclohexylcarbonyl) -4,6-dimethylphenyl) -4-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclopropylcarbonyl) -4,6-dimethylphenyl) -4-methyl-2-thiophenecarboxamide;
3-(((3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- (4-methylthienyl) carbonyl) amino) -2,4,6-trimethylphenylcarbamate;

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- (4-methylthienyl) carbonyl) amino) -2,4,6-trimethylphenylmethyl carbonate ;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-methoxy-2,4,6-trimethylphenyl) acetyl) -4-methyl-3-thiophenesulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-hydroxy-2,4,6-trimethylphenyl) acetyl) -4-methyl-3-thiophenesulfonamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-hydroxy-1-methylethyl) -4,6-dimethylphenyl) -4-methyl- 2-thiophenecarboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-hydroxyethyl) -4,6-dimethylphenyl) -4-methyl-2-thiophenecarboxamide ;

3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2,6-diacetyl) -4-methylphenyl) -4-methyl-2-thiophenecarboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-methoxyacetyl) -4,6-dimethylphenyl) -4-methyl-2-thiophenecarboxamide ;
3- (2-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- (4-methylthienyl) carbonyl) amino) -3,5-dimethylphenyl) -3-oxopropane acid;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-glycolyl-4,6-dimethylphenyl) -4-methyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-methylsulfonyl) phenyl) -4-methyl-2-thiophenecarboxamide;

3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-((methylamino) sulfonyl) phenyl) -4-methyl-2-thiophene Carboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-((dimethylamino) sulfonyl) phenyl) -4-methyl-2-thiophene Carboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-(((methylsulfonyl) amino) carbonyl) phenyl) -4-methyl- 2-thiophenecarboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-fluoroacetyl) -4,6-dimethylphenyl) -4-methyl-2-thiophenecarboxamide ;
N- (6-acetyl-4-methyl-1,3-benzodioxol-5-yl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -4-methyl -2-thiophenecarboxamide;
N- (4-acetyl-6-methyl-1,3-benzodioxol-5-yl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -4-methyl -2-thiophenecarboxamide;

N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -4,5-dimethyl-2-thiophenecarboxamide;
N- (2-benzoyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -4,5-dimethyl-2-thiophenecarboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-hydroxyethaneimidoyl) -4,6-dimethylphenyl) -4,5-dimethyl-2-thiophene Carboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-propionylphenyl) -4,5-dimethyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-isobutyryl-4,6-dimethylphenyl) -4,5-dimethyl-2-thiophenecarboxamide;

3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclohexylcarbonyl) -4,6-dimethylphenyl) -4,5-dimethyl-2-thiophenecarboxamide ;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclopropylcarbonyl) -4,6-dimethylphenyl) -4,5-dimethyl-2-thiophene Carboxamide;
3-(((3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- (4,5-dimethylthienyl) carbonyl) amino) -2,4,6-trimethylphenyl Carbamate;
3-(((3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- (4,5-dimethylthienyl) carbonyl) amino) -2,4,6-trimethylphenyl Methyl carbonate;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-methoxy-2,4,6-trimethylphenyl) acetyl) -4,5-dimethyl-3-thiophenesulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-hydroxy-2,4,6-trimethylphenyl) acetyl) -4,5-dimethyl-3-thiophenesulfonamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-hydroxy-1-methylethyl) -4,6-dimethylphenyl) -4,5- Dimethyl-2-thiophenecarboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-hydroxyethyl) -4,6-dimethylphenyl) -4,5-dimethyl-2- Thiophene carboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2,6-diacetyl) -4-methylphenyl) -4,5-dimethyl-2-thiophene Carboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-methoxyacetyl) -4,6-dimethylphenyl) -4,5-dimethyl-2- Thiophene carboxamide;

3- (2-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- (4,5-dimethylthienyl) carbonyl) amino) -3,5-dimethylphenyl) -3- Oxopropanoic acid;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-glycidyl-4,6-dimethylphenyl) -4,5-dimethyl-2-thiophenecarboxamide;
3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-methylsulfonyl) phenyl) -4,5-dimethyl-2-thiophenecarboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-((methylamino) sulfonyl) phenyl) -4,5-dimethyl-2 -Thiophene carboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-((dimethylamino) sulfonyl) phenyl) -4,5-dimethyl-2 -Thiophene carboxamide;
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-(((methylsulfonyl) amino) carbonyl) phenyl) -4,5- Dimethyl-2-thiophenecarboxamide;

3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (2-fluoroacetyl) -4,6-dimethylphenyl) -4,5-dimethyl-2- Thiophene carboxamide;
N- (6-acetyl-4-methyl-1,3-benzodioxol-5-yl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -4,5 -Dimethyl-2-thiophenecarboxamide; and N- (4-acetyl-6-methyl-1,3-benzodioxol-5-yl) -3-(((4-chloro-3-methyl-5- Isoxazolyl) amino) sulfonyl) -4,5-dimethyl-2-thiophenecarboxamide.
Furthermore, preferred compounds include compounds selected from:

N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-cyclopropyl-2-thiophenecarboxamide;
5-acetyl- (N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide;

N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-cyano-2-thiophenecarboxamide;
N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5- (cyanomethyl) -2-thiophenecarboxamide;
N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-fluoro-2-thiophenecarboxamide;
N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-chloro-2-thiophenecarboxamide; and

  N- (2-acetyl-4,6-dimethylphenyl) -5-chloro-3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -4,5,6,7-tetrahydro -1-Benzothiophene-2-carboxamide.

Preferred compounds are further those W is O or CH _2. Accordingly, the sulfonamides are 2-phenoxycarbonyl-3-sulfonamide, 3-phenoxycarbonyl-2-sulfonamide, 2-phenylacetyl-3-sulfonamide and 3-phenylacetyl-2-sulfonamide derivatives of the above compounds. It is.

  Table 3 lists exemplary compounds of this embodiment and shows that these compounds have activity as endothelin receptor antagonists. More preferred compounds in Table 3 are those with the highest activity, and preferred substituents are on compounds with the highest activity. The data shown in Table 3 is for illustrative and comparison purposes only and is not intended to limit the scope of this embodiment in any way.

^＊結果は２〜５回の実験の平均である。 Table 3

^* Results are the average of 2-5 experiments.

^† Assay performed with incubation at 24 ° C. As described in the Examples, the relatively high temperature incubation reduces the activity by about 1/2 to about 1/10 compared to the activity at 4 ° C.
^- : Data not obtained or measured as% inhibition at 100 μM.
^‖: _ET A / _{ET B} selectivity.

Table 4 lists the oral half-life, bioavailability and in vivo activity of certain exemplary compounds. In vivo activity is measured in a pulmonary hypertension model and is a measure of the activity of a compound at a particular dose. As shown in Table 4, the compounds claimed herein exhibit a higher oral half-life, bioavailability and / or in vivo activity than previously disclosed (eg, PCT international Patent publication WO 96/31492).

^ａ×１０ｃｍ／秒
^ｂ単位は時間
^ｃ単位はμｇ／ｍＬ
^ｄ肺高血圧モデル：
＋＋：５ｍｇ／ｋｇで有効
− ：５ｍｇ／ｋｇで効果なし
＋ ：１５ｍｇ／ｋｇで有効
^ｅ in vivoで０．３ｍｇ／ｋｇで有効 Table 4

^a × 10cm / sec
^b unit is time
^c unit is μg / mL
^d Pulmonary hypertension model:
++: Effective at 5 mg / kg-: No effect at 5 mg / kg +: Effective at 15 mg / kg
^e Effective at 0.3 mg / kg in vivo

C. Preparation of compounds The preparation of neutral (ie, free) sulfonamide compounds having the necessary activity is described in US Pat. Patent applications 08/721183 and 08/847797 and co-owned international PCT application publications WO 96/31492 and WO 97/27979. A representative synthesis is described in the examples. Compounds whose synthesis is not clearly exemplified in this specification or the above patents and published international PCT applications can be replaced by one or more methods described in detail in the Examples by switching to appropriate and readily available reagents. It can be synthesized by changing as usual.

  Salts, acids and other derivatives of the compounds can be synthesized according to the methods described and exemplified herein, or by other methods known to those skilled in the art.

1. Neutral compounds In general, most of this synthesis involves the condensation of a sulfonyl chloride with an aminoisoxazole compound in the presence of sodium hydride in dehydrated pyridine or tetrahydrofuran (THF). Sulfonyl chlorides and aminoisoxazoles are either commercially available or can be synthesized according to the methods described in the Examples or using other methods available to those skilled in the art (eg, US Pat. No. 4,659,369, 4,861,366). No. and 4753672).

  N- (alkylisoxazolyl) sulfonamides are prepared by condensing aminoisoxazole and sulfonyl chloride in dehydrated pyridine in the presence or absence of the catalyst 4- (dimethylamino) pyridine. Can do. N- (3,4-dimethyl-5-isoxazolyl) sulfonamides and N- (4,5-dimethyl-3-isoxazolyl) sulfonamides are equivalents such as 5-amino-3,4-dimethylisoxazole. It can be produced from aminodimethylisoxazole. For example, N- (3,4-dimethyl-5-isoxazolyl) -2- (carbomethoxy) thiophene-3-sulfonamide can be prepared by mixing 2-methoxycarbonylthiophene-3-sulfonyl chloride and 5-amino-3 in dehydrated pyridine. , 4-dimethylisoxazole.

  N- (4-haloisoxazolyl) sulfonamides can be prepared by condensation of amino-4-haloisoxazole and sulfonyl chloride in THF in the presence of sodium hydride as the base. For example, N- (4-bromo-3-methyl-5-isoxazolyl) thiophene-2-sulfonamide is converted to 5-amino-4-bromo-3-methylisoxazole and thiophene in THF in the presence of sodium hydride. Prepared from 2-sulfonyl chloride. N- (4-Bromo-3-methyl-5-isoxazolyl) -5- (3-isoxazolyl) thiophene-2-sulfonamide was treated with 5-amino-4-bromo-3-methylisoxazole and 5- (3- Prepared from isoxazolyl) thiophene-2-sulfonyl chloride.

Alternatively, compounds in which Ar ² is thienyl, furyl and pyrrolyl can be obtained in a tetrahydrofuran (THF) solution containing a base such as sodium hydride in position 3 such as 5-amino-4-bromo-3-methylisoxazole and It can be produced by reacting 5-aminoisoxazole substituted at the 4-position with an appropriate sulfonyl chloride. After the reaction, THF is removed under reduced pressure, the residue is dissolved in water, acidified and extracted with methylene chloride. The organic layer is washed, dried over anhydrous magnesium sulfate, the solvent is distilled off, and the residue is purified by recrystallization using hexane / ethyl acetate to obtain the pure product.

These sulfonamides can also be prepared from the corresponding sulfonyl chloride and aminoisoxazole in pyridine in the presence or absence of catalytic amounts of 4-dimethylaminopyridine (DMAP). In some cases, bissulfonyl compounds may be obtained as the main product or the only product. The bissulfonated product can be easily hydrolyzed to a sulfonamide using a suitable cosolvent such as sodium hydroxide and methanol or tetrahydrofuran, generally at room temperature.
Other examples include:

  (A) N- (4-Bromo-3-methyl-5-isoxazolyl) -2- (N-phenylaminocarbonyl) thiophene-3-sulfonamide is converted to N- (4-Bromo-3-methyl-5-isoxazolyl) ) -2-Carboxythiophene-3-sulfonamide, aniline and 1-ethyl-3 ′-[3-dimethylaminopropyl] carbodiimide (EDCI). N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(4-methoxyphenyl) aminocarbonyl] thiophene-3-sulfonamide was converted to 4-methoxyaniline, N, N′-diisopropylethylamine and N Prepared from-(4-bromo-3-methyl-5-isoxazolyl) -2-carboxylthiophene-3-sulfonamide. N- (4-Bromo-3-methyl-5-isoxazolyl) -2- (benzylaminocarbonyl) thiophene-3-sulfonamide is converted to N- (4-Bromo-3-methyl-5-isoxazolyl) -2-carboxyl Prepared from thiophene-3-sulfonamide and benzylamine according to the method described above.

  N- (4-Bromo-3-methyl-5-isoxazolyl) -2-carboxylthiophene-3-sulfonamide is a combination of 5-amino-4-bromo-3-methylisoxazole and 2- (carbomethoxy) thiophene-3. Prepared from N- (4-bromo-3-methyl-5-isoxazolyl) -2- (carbomethoxy) thiophene-3-sulfonamide obtained from condensation of sulfonyl chloride.

  (B) N- (4-Bromo-3-methyl-5-isoxazolyl) -1- (4′-isopropylphenyl) pyrrole-2-sulfonamide and N- (4-Bromo-3-methyl-5-isoxazolyl) -1- (4′-isopropylphenyl) pyrrole-3-sulfonamide was converted to 5-amino-4-bromo-3-methylisoxazole and 1- (4′-isopropylphenyl) pyrrole-2-sulfonyl chloride and 1- And a mixture of (4′-isopropylphenyl) pyrrole-3-sulfonyl chloride. These sulfonyl chlorides were prepared from 1- (4'-isopropylphenyl) pyrrole-2-sulfonic acid, phosphorus oxychloride and phosphorus pentachloride. 1- (4'-Isopropylphenyl) pyrrole-2-sulfonic acid was prepared from 1- (4'-isopropylphenyl) pyrrole and chlorosulfonic acid. 1- (4'-Isopropylphenyl) pyrrole was prepared from 4-isopropylaniline and 2,5-dimethoxytetrahydrofuran.

2. Neutral Compound Salts Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by the methods illustrated or other methods known to those skilled in the art. As exemplified herein, in the case of organic salts, N, N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N An organic base such as benzylphenethylamine, 1-parachlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine or tris (hydroxymethyl) aminomethane in an equimolar amount of sulfone Can be mixed with amides. Thereafter, crystallization, precipitation, solution concentration, lyophilization, spray drying, chromatography such as, but not limited to, normal phase and reverse phase chromatography or resin chromatography, or others known to those skilled in the art. It is considered that the desired salt can be obtained by recovering the salt by the above method. Pharmaceutically acceptable cationic salts can be prepared by reacting the acid form with a suitable base.

3. Hydrophobic Sulfonamide Salts A method for producing an alkali metal salt of a hydrophobic sulfonamide endothelin activity regulator is provided. More particularly, a process for the preparation of sodium salts of such sulfonamides is provided. Each method includes a step of dissolving free sulfonamide in an organic solvent in the presence of a saturated aqueous solution of an alkali metal salt, and a step of recovering and purifying the sulfonamide salt.

Sulfonamides that convert to alkali metal salts can be prepared by methods known in the art (see, for example, US Pat. Nos. 5,591,761 and 5,594,021). As an example, N ² -methoxy-N ² -methyl-3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl) -2-thiophenecarboxamide was synthesized in an organic solvent with 6-methylbenzo [ d] [1,3] dioxolyl-5-methylmagnesium chloride to give 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5 -Yl) acetyl) -3-thienylsulfonamido) isoxazole is obtained as a crude product, which is purified by preparative HPLC.

Method for Producing Alkali Metal Salt A separate method for producing the salt is provided and exemplified below (see Example 7). That is, the method includes (a) mixing 5-chloromethyl-6-methylbenzo [d] [1,3] dioxole and activated magnesium in tetrahydrofuran; (b) adding N ² -methoxy- to the reaction mixture. Adding N ² -methyl-3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl) -2-thiophenecarboxamide; (c) mixing the mixture from step (b) with concentrated inorganic acid and There are steps of diluting the organic solvent in order to form an aqueous layer and an organic layer; and (d) dehydrating the organic layer and distilling off the solvent to form a residue.

  This salt formation process begins with the step of dissolving the free sulfonamide in an organic solvent. Suitable organic solvents for use in the method are known in the art. Examples of preferred organic solvents are ethyl acetate, methyl t-butyl ether, methylene chloride, THF, ether, acetonitrile, dioxane and chloroform. Ethyl acetate is the most preferred organic solvent.

  The formation of the alkali metal salt proceeds by exposing an organic solvent containing free sulfonamide to a saturated solution of the alkali metal salt. The particular salt used will depend on the desired sulfonamide salt to be formed. Suitable alkali metals for use in the method of the present invention are known in the art and include sodium, potassium, calcium, magnesium and the like. Sodium and calcium are preferred alkali metals for the preparation of useful sulfonamide salts for pharmaceutical compositions. Sodium is most preferred. The anion component of the salt is known in the art and includes carbonate ions, phosphate ions, bicarbonate ions, nitrate ions, hydroxide ions, and combinations thereof. Anions such as carbonate ion, bicarbonate ion and hydroxide ion are preferred. Bicarbonate ions are more preferred. The alkali metal salt used to form the sulfonamide is in the form of a fairly concentrated aqueous solution. It is preferred to use a saturated solution. Means for producing saturated alkali metal salt solutions are known in the art. The biphasic mixture is agitated by the desired number of methods such as shaking, agitation, sonication and the like. After separating the layers, the aqueous phase is removed.

The recovery of the product from the organic solvent is performed using means known in the art such as crystallization and filtration. In one embodiment, the organic solvent containing the sulfonamide salt is washed with a concentrated salt solution, wherein the alkali metal is the same as that used for salt formation. When the alkali metal salt is sodium, examples of cleaning solutions include sodium chloride (eg, brine) or a concentrated solution of sodium bicarbonate. Once the protonated sulfonamide is converted to the salt form, it is important to use a concentrated (greater than about 3% by weight) salt wash. Surprisingly, alkali metal sulfonamide salts are more soluble in organic solvents than in saturated alkali metal solutions. A dilute solution of salt (eg, 1/2 concentration brine) or water for organic solvent washing can cause product imbalance between the water and the organic layer, resulting in material loss. After washing, the product solution can be dehydrated and concentrated to obtain the crude product, for example as a residue. In a preferred embodiment, dehydration is performed with Na ₂ SO ₄ or MgSO ₄ and concentration is performed under reduced pressure.

  The residue is further recovered and purified using recrystallization. According to this embodiment, the product is dissolved in an organic, non-water miscible solvent. Such solvents are well known in the art. Examples of preferred such solvents are ethers and halomethanes such as methylene chloride and chloroform. Such solvents can be used in combination. The resulting crystalline product can be isolated from the organic solvent by filtration. The recovered product can be washed one or more times with a non-water miscible organic solvent. 4-Chloro-3-methyl-5 (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole sodium according to the disclosed method A detailed description of the production of the salt will be given later in the examples.

  The sulfonamide salts provided in the present invention can be converted back to the free sulfonamide form and further purified by this method. The sulfonamide salt is dissolved in an aqueous solvent (eg water) and filtered. Preferably, the filtration is performed through a plurality of filter paper layers. It appears that no negative pressure or suction is required to complete the filtration. In some cases, due to the large amount of impurities that are not soluble in water (10% or more), the speed of the filtration process is reduced. The problem can be avoided by using a large area filter paper during filtration. Usually, if the purity of the crude salt is 90% or more, there is no problem in filtration.

An isolated salt, usually in the form of a cloudy solution, is converted to an acid by exposing the salt to a concentrated inorganic acid. Suitable acids include hydrochloric acid (HCl), sulfuric acid (H ₂ SO ₄ ), nitric acid (H ₂ NO ₃ ), and the like. Acid treatment is continued until the pH of the product solution is about 1.5 to about 2.5. The acid treatment is preferably performed at a temperature of about 10 ° C. or less. The product may precipitate as a bowl-like hard-filtrate during acid treatment. Slow addition of a slight excess of acid causes the product to form a fine filterable precipitate. The precipitate is filtered, washed with water until neutral, and pressed on filter paper to remove excess moisture. The resulting free acid is usually> 95% pure as determined by HPLC. The purified sulfonamide can then be converted to an alkali metal salt by the procedure described above.

  By carrying out the method provided in the present invention, the reaction time can be shortened and a product having a higher purity than that obtained by other methods can be obtained. Direct isolation of the sulfonamide salt can be accomplished by mixing the product with a concentrated alkaline salt solution and an organic solvent. A surprisingly important finding is that as long as the aqueous layer contains a high concentration of salt, the sulfonamide salt remains in the organic layer rather than in the aqueous layer as expected. Thereby, the salt can be isolated directly, which can be further purified by conversion to the free sulfonamide and reconversion to the salt and recrystallization. This discovery is important in synthesizing high-purity sulfonamide salts in large quantities.

4). Other derivatives Prodrugs and other derivatives of compounds suitable for human administration can also be designed and manufactured by methods known to those skilled in the art (eg, Nogrady (1985) Medicinal Chemistry A Biochemical Approach , Oxford University Press , New York, pp.388-392).

The compounds described herein were subjected to synthesis and activity tests in in vitro assays and in some cases in in vivo animal models. From each magnetic resonance spectroscopy (NMR), mass spectral analysis, infrared spectral analysis, and high performance liquid chromatography analysis, the synthesized compound has a structure consistent with the structure expected for such a compound, greater than about 98% It was found to have a purity of Any of the compounds exemplified or described herein have shown activity as endothelin antagonists.

D. Sulfonamide and Sulfonamide Salt Formulations Sulfonamide and sulfonamide salt formulations described above are provided herein. The formulations prepared according to the methods described below are compositions for administering pharmaceutically acceptable derivatives, particularly the salts of the sulfonamide compounds provided by the present invention. Such salts, in particular sodium salts, are particularly suitable for oral and parenteral administration, since it has been observed that the salts have excellent stability compared to the neutral form. Such compositions include solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, dry powders for inhalers, sustained release formulations and other suitable formulations. Preferably the composition takes the form of a pill or tablet. Methods for producing tablets, capsules and other such formulations are known to those skilled in the art (see, eg, Ansel HC (1985) Introduction to Pharmaceutical Dosage Forms , 4th Edition, pp. 126-163).

Clearly, pharmaceutically acceptable acids, esters, salts and prodrug derivatives of these compounds are preferred in the formulations of the present invention. Suitable for use in the present invention for the preparation of the above formulations are sodium salts, particularly sodium salts in which Na ⁺ is the counter ion.

  In formulations, an effective concentration of one or more pharmaceutically acceptable derivatives is admixed with a suitable pharmaceutical carrier or vehicle. Preferably, the sulfonamide compound is derivatized as the corresponding salt, preferably the sodium salt, and then formulated according to the method described above. The salt concentration of the compound in the formulation is effective in delivering an amount that, by administration, ameliorates the symptoms of endothelin-mediated disease. Typically, the composition is formulated for single administration. To formulate a composition, a predetermined proportion of the compound is dissolved, suspended, dispersed or otherwise mixed in a predetermined medium at an effective concentration that will alleviate or improve the condition to be treated.

  Suitable pharmaceutical carriers or vehicles for administration of the compounds provided by the present invention include those known to those skilled in the art to be suitable for a particular dosage form. Furthermore, the compounds can be formulated as a single active pharmaceutical ingredient in the composition or can be combined with other active ingredients. Liposomal suspensions such as tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. They can be prepared according to methods known to those skilled in the art. For example, a liposome preparation can be produced according to the method described in US Pat. No. 4,522,811.

The active compound as a salt, preferably a sodium salt, is included in a pharmaceutically acceptable carrier in an amount sufficient to produce a therapeutically useful effect without undesirable side effects on the patient receiving it. By testing compounds in known in vitro and in vivo systems, therapeutically effective concentrations are empirically determined (eg, US Pat. No. 5,114,918 to Ishikawa et al; EP A1 to BANYU PHARMACEUTICAL CO., LTD. 0 436 189 (October 7, 1991); Borges et al . (1989) Eur. J. Pharm. , 165 : 223-230; Filep et al. (1991) Biochem . Biophys . Res . Commun ., 177 : 171-176) and can then be extrapolated to determine the human dose.

  The concentration of the active compound sodium salt in the pharmaceutical composition is determined by the absorption rate, deactivation rate and excretion rate of the active compound, the physicochemical properties of the active compound, the dosing schedule and dosage, as well as others known to those skilled in the art. It depends on the elements of. For example, the amount administered is an amount sufficient to treat the symptoms of hypertension. The effective amount for treatment of endothelin mediated disorders is expected to be higher than the amount of sulfonamide compound that would be administered for the treatment of bacterial infection.

  Typically, a therapeutically effective dose should give a serum concentration of active ingredient of about 0.1 ng / mL to about 50-100 μg / mL. The pharmaceutical composition should typically give a dose of about 0.001 mg to about 2000 mg / kg / day of the compound. A pharmaceutical unit formulation is prepared to provide from about 1 mg to about 1000 mg, preferably from about 10 mg to about 500 mg of the essential active ingredient or combination of essential ingredients per unit dosage.

The active ingredient can be administered at once, or can be divided into small portions and administered at intervals. Obviously, the exact dose and duration of administration depends on the disease to be treated and can be determined empirically using known test methods or by extrapolation from in vivo or in vitro test data. It should be noted that concentration and dose values can also vary depending on the severity of the condition to be alleviated. It should also be understood that in a particular patient, the specific method of administration may be determined over time according to the patient's needs and the individual's professional judgment overseeing the administration of the composition. The concentration ranges described herein are for illustrative purposes only and are not intended to limit the scope or actual use of the claimed compositions.

  Preferred derivatives include acid, ester and prodrug forms. The derivative is selected to be in a more stable form than the corresponding neutral compound. Preferred are pharmaceutically acceptable salts, N, N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-parachlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris (hydroxymethyl) aminomethane, etc. (but are not limited thereto) ) Amine salts; alkali metal salts such as, but not limited to lithium, potassium and sodium; alkaline earth metals such as but not limited to barium, calcium and magnesium Transition metal salts such as, but not limited to iron, zinc, gold and silver; aluminum, sodium hydrogen phosphate, disodium phosphate or bismuth salts, but not limited to There are other metal salts (but not limited to), preferably sodium salts, more preferably sodium salts, and further sulfonamide compounds or pharmaceutically acceptable esters of the compounds Mineral salts such as but not limited to hydrochloride and sulfate of other derivatives, acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, Also included are organic acid salts such as but not limited to butyrate, valerate and fumarate. . More preferred salts include sodium salts such as, but not limited to, sodium hydrogen phosphate and sodium salts, most preferably sodium salts.

  As such, an effective concentration or amount of one or more compounds provided herein or a pharmaceutically acceptable derivative thereof is a pharmaceutical carrier or vehicle suitable for systemic, topical or local administration. Mix to form a pharmaceutical composition. The compound is included in an amount effective to ameliorate or treat the endothelin-mediated disorder intended for treatment. The concentration of the active compound in the composition will depend on absorption rate, deactivation rate and excretion rate of the active compound, schedule of administration, dosage, particular formulation, and other factors known to those skilled in the art.

  The compound is to be administered by a suitable route such as oral, parenteral, rectal and topical and topical depending on the disorder being treated. For example, in the case of treatment of ocular disorders such as glaucoma, preparations for intraocular injection and intravitreal injection are conceivable. For oral administration, capsules and tablets are currently preferred. For parenteral administration, regeneration of the lyophilized powder according to the methods described herein is preferred. Compounds in liquid, semi-liquid or solid form are formulated in a manner suitable for each route of administration. Preferred dosage forms include parenteral and oral administration.

  For solutions or suspensions for parenteral, intradermal, subcutaneous or topical administration, sterile diluents such as water for injection, physiological saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol and other synthetic solvents; Antibacterial agents such as benzyl alcohol and methylparabens: antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetate, citrate and phosphate; and chloride Any of the components of tonicity modifiers such as sodium or glucose can be included. The parenteral preparation can be enclosed in ampoules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.

  When the solubility of the compound is insufficient, a method for solubilizing the compound can be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of co-solvents such as dimethyl sulfoxide (DMSO), the use of surfactants such as Tween, or dissolution in aqueous sodium bicarbonate. It is not done. Derivatives of the compounds, such as prodrugs of the compounds, can also be used in the formulation of effective pharmaceutical compositions.

  When the sodium salt of the sulfonamide compound is incorporated or added, the resulting mixture can be a solution, suspension, emulsion salt, and the like. The form of the resulting mixture depends on a number of factors such as the intended dosage form and the solubility of the compound in the particular carrier or vehicle. The effective concentration is sufficient to ameliorate the symptoms of the disease, disorder or condition to be treated and can be determined empirically.

  The formulation comprises tablets, capsules, pills, powders, dry powders for inhalers, granules, sterile non-septics containing a suitable amount of said compound, in particular a pharmaceutically acceptable salt of said compound, preferably the sodium salt of said compound. Provided for administration to humans and animals in unit dosage forms, such as solutions or suspensions for oral administration, solutions or suspensions for oral administration, oil-water emulsions. Pharmaceutically therapeutically active compounds and derivatives of the compounds are typically formulated and administered in unit- or multi-dose formulations. A unit dosage form as used herein refers to a physically discrete unit suitable for human and animal patients, individually packaged in a manner known in the art. Each unit formulation contains a predetermined quantity of therapeutically active compound sufficient to produce the desired therapeutic effect, along with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dosage forms include ampoules and syringes, individually packaged tablets or capsules. A multiple dose formulation is a plurality of the same unit formulation packaged in a single container and is administered in separate unit formulations. Examples of multi-dose formulations include vials, tablet or capsule bottles, or pint or gallon bottles. Thus, a multi-dose formulation is a plurality of unit formulations that are not separated by packaging.

  The composition includes, together with active ingredients, diluents such as lactose, sucrose, dicalcium phosphate or carboxymethyl cellulose; lubricants such as magnesium stearate, calcium stearate and talc; and starch, acacia gelatin gum and the like Natural gums, glucose, molasses, polyvinylpyrrolidone, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those skilled in the art . Liquid pharmaceutically administrable compounds include, for example, an active compound as defined above and an optionally added pharmaceutical adjuvant dissolved in a carrier such as water, saline, aqueous glucose solution, glycerin, glycols, ethanol, It can be prepared by dispersing or otherwise mixing to form a solution or suspension. If desired, the pharmaceutical composition to be administered may further comprise a moisturizer such as acetate, sodium citrate, cyclodextrin derivative, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate and other such agents. Small amounts of nontoxic auxiliary substances such as spreading agents, emulsifying or solubilizing agents, pH buffering agents and the like can be included. The actual preparation of such formulations is known or apparent to those skilled in the art (see, eg, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975). The composition or formulation to be administered will, in each case, contain the active compound in an amount sufficient to alleviate the symptoms of the patient being administered.

  A preparation or composition containing the active ingredient in the range of 0.005% to 100% and the remaining part being a non-toxic carrier can be prepared. For oral administration, for example, pharmaceutical mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talc and the like are usually used. The excipient is incorporated to formulate a pharmaceutically acceptable non-toxic composition. Such compositions include solutions, suspensions, tablets, capsules, powders, dry powders for inhalers and, for example, implants and microcapsule administration systems and collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid And sustained-release preparations such as, but not limited to, biodegradable and biocompatible polymers such as polyorthoesters and polylactic acid. Methods for preparing these formulations are known to those skilled in the art. The contemplated compositions can contain 0.01% to 100% active ingredient, preferably 0.1 to 95%, typically 75 to 95%.

  Salts of active compounds, preferably sodium salts, can be formulated with carriers that will protect the compound against rapid elimination from the body, such as a sustained release formulation or coating. The formulation can contain other active compounds to achieve the desired combination of properties. Compounds of formula I or pharmaceutically acceptable salts and derivatives thereof as described herein advantageously treat one or more of the diseases or medical conditions described above for therapeutic or prophylactic purposes. Can be administered with other drugs known in the art to be effective. For example, β-adrenergic blockers (eg, atenolol), calcium channel blockers (eg, nifedipine), angiotensin converting enzyme (ACE) inhibitors (eg, lisinopril), diuretics (eg, furosemide or hydrochlorothiazide) ), Endothelin converting enzyme (ECE) inhibitors (eg, phosphoramidon), neutral endopeptidase (NEP) inhibitors, HMGCoA reductase inhibitors, nitric oxide donors, antioxidants, vasodilators, dopamine agonists, There are neuroprotective drugs, asteroids, β-agonists, anticoagulants or thrombolytic agents. It should be understood that such combination therapy constitutes another aspect of the compositions and treatment methods provided herein.

1. Preparations for oral administration Oral pharmaceutical preparations are solid, gel or liquid. Solid preparations are tablets, capsules, granules, mixed powders. Types of oral tablets include compression / chew lozenges and tablets, which can be enteric coated, sugar coated or film coated. Capsules can be hard or soft gelatin capsules, and granules and powders can be provided in non-foamed or foamed formulations in combination with other ingredients known to those skilled in the art.

  In certain embodiments, the formulation is a solid formulation, preferably a capsule or tablet. Tablets, pills, capsules, troches and the like can contain components such as binders, diluents, disintegrants, lubricants, lubricants, sweeteners and flavoring agents, or compounds of similar nature.

  Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, gum arabic, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, stone mushrooms and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Lubricants include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, seaweed acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Colorants include, but are not limited to, water-insoluble FD and C dyes that have been approved and guaranteed, mixtures thereof; and water-insoluble FD and C dyes suspended on alumina hydrate. It is not something. Sweetening agents include sucrose, lactose, mannitol and artificial sweeteners such as sodium cyclamate and saccharin, and many spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and artificial mixtures of compounds that provide a pleasant sensation such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monostearate, diethylene glycol monolaurate and polyoxyethylene laural ether. Enteric coatings include fatty acids, fats, waxes, shellac, aminated shellac and cellulose acetate phthalates. Film coating agents include hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

  If oral administration is desired, the salt of the compound could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated with an enteric coating that maintains integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such ingredient.

  When the unit preparation is a capsule, it can contain a liquid carrier such as fatty oil in addition to the above types of materials. In addition, the unit formulation can contain various other materials that change the physical form of the unit formulation, such as, for example, coatings of sugar and other enteric solvents. The compound can also be administered as a component of an elixir, suspension, syrup, wafer, spray, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The active material can also be mixed with other active materials that do not adversely affect the desired action, or with materials that assist the desired action, such as antacids, H ₂ blockers and diuretics. For example, when the compound is used for the treatment of asthma or hypertension, it can be used in combination with other bronchodilators and antihypertensive agents, respectively. The active ingredient is a compound as described herein or a salt of the compound. A relatively high concentration of active ingredient up to about 98% by weight can be included.

  Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. With enteric coating, enteric-coated tablets are resistant to the action of gastric acid and dissolve or disintegrate in neutral or alkaline intestines. Sugar-coated tablets are compressed tablets with various layers of pharmaceutically acceptable substances. Film-coated tablets are compressed tablets that are coated with a polymer or other suitable coating agent. Multiple compressed tablets are compressed tablets made by multiple compression cycles utilizing the aforementioned pharmaceutically acceptable substances. Coloring agents can also be used in the above formulations. Flavoring and sweetening agents are used in compressed tablets, dragees, multiple compressed tablets and chewable tablets. Flavoring and sweetening agents are particularly useful in chewing and lozenge formulations.

  Liquid oral formulations include aqueous solutions, emulsions, suspensions, solutions and / or suspensions regenerated from non-foamed granules and foamed formulations regenerated from foamed granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions include oil-water or water-oil emulsions.

  An elixir is a clear, hydroalcoholic preparation with a sweetening agent. A pharmaceutically acceptable carrier used in elixirs is a solvent. The syrup is a concentrated aqueous solution of sugar such as sucrose, and can contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of microdroplets throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifiers and preservatives. For suspensions, pharmaceutically acceptable suspending and preserving agents are used. Pharmaceutically acceptable substances used in non-foamable granules that become liquid oral formulations upon regeneration include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable materials for use in effervescent granules that can be regenerated into liquid oral formulations include organic acids and carbon dioxide sources. In any of the above formulations, colorants and flavoring agents are used.

  Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweeteners such as sodium cyclamate and saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Examples of the carbon dioxide source include sodium bicarbonate and sodium carbonate. Colorants include approved and guaranteed water-soluble FD and C dyes and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits and artificial mixtures of compounds that produce a pleasant taste.

  For solid formulations, solutions or suspensions such as propylene carbonate, vegetable oils or triglycerides are preferably enclosed in gelatin capsules. Such solutions and their preparation and encapsulation are disclosed in US Pat. Nos. 4,328,245, 4,409,239 and 4,410,545. In liquid formulations, for example, a solution of polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (eg, water) so that it can be readily measured upon administration.

  Alternatively, liquid or semisolid oral formulations can be prepared by dissolving or dispersing the active compound or salt in a vegetable oil, glycols, triglycerides, propylene glycol esters (eg, propylene carbonate) and other such carriers. It can be prepared by encapsulating the solution or suspension in a hard or soft gelatin capsule shell. Other useful formulations include those described in US Pat. Nos. Re28819 and 4358603.

  In one embodiment, the material is a solid formulation, preferably a capsule or tablet. In a preferred embodiment, the formulation comprises 10-100% by weight, preferably 50-95% by weight, more preferably 75-85% by weight, most preferably 80-85% by weight of one or more sulfonamides or sulfonamide salts, Preferably, one or more sodium hydrogen phosphates or sodium salts, more preferably sodium salts of one or more sulfonamide compounds of formula I; such as about 0-25%, preferably 8-15% lactose or microcrystalline cellulose, etc. Diluent or binder; about 0-10%, preferably about 3-7% of modified starch or cellulose polymer, especially croscarmellose sodium (croscarmellose sodium NF is commercially available under the name AC-DI-SOL. (FMC Corporation, Philadelphia, PA) and sodium starch glycolate Disintegrating agents such as bridges sodium carboxymethylcellulose; and solid formulations comprising a lubricant, such as 0-2% of magnesium stearate, talc and calcium stearate, preferably capsules or tablets. Disintegrants such as croscarmellose sodium and sodium starch glycolate disintegrate the cellulosic substrate rapidly after dissolution of the coating polymer and immediately release the active agent. In all embodiments, the exact amounts of active and adjunct ingredients can be determined empirically and depends on the route of administration and the disorder being treated.

  In one example embodiment, the formulation comprises about 80-90%, preferably about 83%, of one or more sodium salts of one or more sulfonamide compounds of formula I; about 10-15%, preferably about 11%. Diluent or binder such as lactose or microcrystalline cellulose; about 1-10%, preferably about 5% disintegrant, such as sodium croscarmellose or sodium starch glycolate; and about 0.1-5%, preferably Capsules containing about 1% lubricant such as magnesium stearate. Solid formulations for administration as tablets are also contemplated by the present invention.

  In one example of a preferred embodiment, the formulation comprises 83% one or more sodium salts of one or more sulfonamide compounds; 11% microcrystalline cellulose; 5% disintegrant such as croscarmellose sodium or sodium starch glycolate. As well as capsules containing 1% magnesium stearate.

  The above embodiments can also be formulated in the form of tablets that may be appropriately coated. Tablets contain the composition described herein.

  In any embodiment, tablet and capsule formulations may be coated according to methods known to those skilled in the art to change or maintain dissolution of the active ingredient. Thus, for example, they can be coated with conventional enteric coating agents such as phenyl salicylate, wax and cellulose acetate phthalate.

2. Parenteral administration, characterized by injections , solutions and emulsions, usually subcutaneous injections, intramuscular injections or intravenous injections, is also contemplated by the present invention. Injectables can be prepared in conventional forms as liquid solutions or suspensions, solid formulations suitable for liquid preparation or suspension prior to injection, or emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerin or ethanol. For example, if desired, the pharmaceutical composition to be administered may be a wetting or emulsifying agent such as sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins, pH buffering agents, stabilizers, dissolution enhancing agents. Small amounts of nontoxic auxiliary substances such as agents and other such agents may also be included. Slow or sustained release implantation (eg, see US Pat. No. 3,710,795) is also contemplated by the present invention to maintain a constant dose level. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature of the composition, as well as the activity of the compound and the needs of the patient.

  Parenteral administration of the formulation includes intravenous administration, subcutaneous administration and intramuscular administration. For preparations for parenteral administration, sterile solutions for injection; sterile dry soluble preparations such as freeze-dried powders described herein for combination with a solvent immediately before use, such as tablets for injection; sterile injection suspensions Aseptic dry insoluble preparations to be combined with the medium just before use; as well as sterile emulsions. The liquid agent can be aqueous or non-aqueous.

  For intravenous administration, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickeners and solubilizers such as glucose, polyethylene glycol and polypropylene glycol, and mixtures thereof. There is.

  Pharmaceutically acceptable carriers used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers. Sequestering or chelating agents as well as other pharmaceutically acceptable substances.

  Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water for injection, glucose / lactic acid-added Ringer's injection, and the like. Non-aqueous parenteral vehicles include fixed oils of plant origin, cottonseed oil, corn oil, sesame oil and peanut oil. Parenteral preparations packaged in multi-dose containers must contain an antibacterial agent at a bacteriostatic or fungistatic concentration, including phenols or cresols, mercury, benzyl alcohol, chlorobutanol , Methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and glucose. Buffering agents include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifiers include polysorbate 80 (Tween 80). Examples of the metal ion sequestering or chelating agent include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible media, and sodium hydroxide hydrochloric acid, citric acid or lactic acid for pH adjustment.

  The concentration of the pharmaceutically active compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The exact dose will depend on the age, weight and condition of the patient or animal as is known in the art.

  Unit dose parenteral formulations are placed in ampoules, vials or syringes with needles. Any formulation for parenteral administration must be sterile, as is known and practiced in the art.

  By way of example, intravenous or arterial infusion of a sterile aqueous solution containing an active compound is an effective dosage form. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

Injectables are for local and systemic administration. Typically, a therapeutically effective dose is formulated so that the active compound for the administered tissue is included at a concentration of about 0.1% to about 90% by weight or more, preferably greater than 1% by weight. To. The active ingredient can be administered at once, or can be divided into small portions and administered at intervals. The exact dose and duration of administration will depend on the tissue to be treated and can obviously be determined empirically using known test methods or by extrapolation from in vivo or in vitro test data. It should be noted that concentration and dose values may also vary with the age of the patient receiving the administration. It should also be understood that in a particular patient, the specific dosage regimen can be determined over time according to the patient's needs and the professional judgment of the individual administering the formulation or overseeing the administration of the composition. Accordingly, the concentration ranges set forth herein are for illustrative purposes only and do not limit the scope or actual use of the claimed compositions.

  The compound can be suspended in micronized or other suitable form or derivatized to obtain a more soluble active substance or a prodrug. The form of the resulting mixture depends on a number of factors such as the intended dosage form and the solubility of the compound in the particular carrier or vehicle. The effective concentration is sufficient to improve the symptoms of the condition and can be determined empirically.

Certain sodium salts of the sulfonamides provided by the present invention, particularly those in which R ⁸ is phenylacetyl, have been found to exhibit increased stability compared to formulations containing neutral compounds. The data shown in Table 5 is 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamide. ) Reflects that the aqueous solution of sodium hydrogen phosphate and sodium salt of isoxazole has improved stability compared to neutral compounds. These salts further exhibit higher solubility in aqueous media than neutral compounds. As can be seen from Table 5, the sodium hydrogen phosphate salt is more stable in the LABRASOL solution than the neutral compound. The sodium salt was found to be as stable in certain aqueous formulations as sodium hydrogen phosphate.

Table 5

time after ^a formulation preparation
^b high performance liquid was determined by chromatographic analysis of 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienyl sulfone Amido) isoxazole percent

  In many cases, solutions of sodium salts, such as sodium salts and sodium hydrogen phosphate, exhibit higher stability compared to neutral compounds. These salts further exhibit higher solubility in aqueous media than neutral compounds.

3. Lyophilized powder Of particular interest in the present invention are lyophilized powders that can be regenerated and administered as solutions, emulsions and other mixtures. It can also be formulated as a solid or a gel.

  In a particular embodiment, a sodium hydrogen phosphate or sodium salt, preferably sodium salt formulation of a sulfonamide compound is provided that has a high stability compared to a formulation of neutral sulfonamides. Specifically, a sulfonamide sodium salt formulation as a sterile lyophilized powder is provided. The powder was found to be more stable than the neutral sulfonamide formulation.

  A sterile lyophilized powder is prepared by dissolving the sodium salt in a sodium phosphate buffer containing glucose and other suitable excipients. The solution is aseptically filtered and then lyophilized under standard conditions known to those skilled in the art to provide the desired formulation. That is, the lyophilized powder contains about 1 to 20%, preferably about 5 to 15% of glucose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose and other suitable drugs, citrate, phosphorus Prepared by dissolving in a suitable buffer, such as sodium or potassium acid or other such buffer known to those skilled in the art, typically at a neutral pH. Next, a particular salt of sulfonamide, preferably a sodium salt (about 1 g of salt per 10-100 g of buffer, typically 1 g / 30 g), is preferably added to room temperature, more preferably about room temperature. Add at 30-35 ° C and stir until it dissolves. The resulting mixture is diluted with additional buffer (thus reducing the resulting salt concentration to about 10-50%, typically about 15-25%). The resulting mixture is aseptically filtered or processed to remove particulates, ensuring sterility, and aliquoted into vials for lyophilization. Each vial contains a single dose (100-500 mg, preferably 250 mg) or multiple doses of the sulfonamide salt. The lyophilized powder can be stored under appropriate conditions, such as at about 4 ° C. to room temperature. Details of the example procedure are described in the examples.

  By regenerating this lyophilized powder with water for injection, a preparation for parenteral administration of sodium salt of sulfonamide can be obtained. For regeneration, about 1-50 mg, preferably 5-35 mg, more preferably about 9-30 mg is added per mL of sterile water or other suitable carrier. The exact amount will depend on the indication being treated and the particular compound. Such an amount can be determined empirically.

  In one embodiment, the formulation contains a lyophilized solid comprising one or more sodium hydrogenphosphate or sodium salts, preferably sodium salts, of one or more sulfonamide compounds of formula I, and further comprising one or more of the following Ingredients can be included.

Buffering agents such as sodium or potassium phosphate or citrate;
Solubilizers such as LABRASOL, DMSO, bis (trimethylsilyl) acetamide, ethanol, propylene glycol (PG) or polyvinylpyrrolidone (PVP); and sugars or carbohydrates such as sorbitol or glucose.

  In a more preferred embodiment, the formulation comprises one or more sodium hydrogen phosphates or sodium salts, preferably sodium salts of one or more sulfonamide compounds of formula I; buffers such as sodium or potassium phosphate or citrate; As well as sugars or carbohydrates such as sorbitol or glucose.

  In a most preferred embodiment, the formulation contains one or more sodium salts of a sulfonamide compound; a sodium phosphate buffer; and glucose. The preparation of the formulation is illustrated in the examples.

4). Topical administration Mixtures for local administration are prepared according to the methods described for local and systemic administration. The resulting mixture can be a solution, suspension, emulsion, etc., cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, Formulate as an aerosol, irrigation, spray, suppository, bandage, dermatology or other formulation suitable for topical administration.

  Sodium salts and other derivatives of the compounds can be formulated as aerosols for topical administration such as inhalation (eg, US patents describing aerosols for steroid administration useful in the treatment of inflammatory diseases, particularly asthma) 4044126, 4414209 and 4364923). These formulations for administration to the respiratory tract can be in the form of aerosols or solutions for nebulizers, or a fine particulate for ventilation, either alone or in combination with an inert carrier such as lactose. In such cases, the particle size of the formulation is typically less than 50 microns, preferably less than 10 microns.

  Sodium salts of the compounds may be administered locally in the form of gels, creams and lotions, for topical administration to the mucous membranes such as the skin and the eyeball, and further to the eyeball, or in the tank or spinal cord. It can be formulated for topical administration. Topical administration is conceived for transdermal administration, conceivable for administration to the eyeball or mucosa, or for inhalation therapy. Solutions of the active compound either alone or in combination with other pharmaceutically acceptable excipients can also be administered.

  The solutions, especially ophthalmic solutions, can be formulated as 0.01% -10% isotonic solutions (pH about 5-7) containing appropriate salts.

5. Manufacture Articles Derivatives of the compound, in particular salts, acids, esters and preferably sodium salts, are included in the packaging material; antagonizing the effects of endothelin, improving symptoms of endothelin-mediated disorders, or about 10 μM. A sodium salt of a compound provided herein that is effective in inhibiting the binding of an endothelin peptide to an ET receptor with an IC ₅₀ value of less than; and the compound or sodium salt of the compound may antagonize the effects of endothelin, endothelin It can be packaged as an article of manufacture having a label indicating that it is used to treat an intervening disorder or to inhibit the binding of an endothelin peptide to an ET receptor.

6). Other routes of administration Other routes of administration, such as topical administration, transdermal patches, and rectal administration, are also contemplated by the present invention, depending on the condition of the subject to be treated.

  For example, pharmaceutical preparations for rectal administration are rectal suppositories, capsules and tablets for systemic effect. In this case, rectal suppositories are used as mean solids for insertion into the rectum, which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles and agents for increasing the melting point. Examples of bases include cocoa butter (cocoa butter), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and suitable mixtures of mono, di and triglycerides of fatty acids. Examples of drugs that increase the melting point of suppositories include whale wax and wax. Rectal suppositories can be manufactured either by the compressed or molded method. The typical weight of a rectal suppository is about 2-3 g.

  Tablets and capsules for rectal administration are manufactured by the same method using the same pharmaceutically acceptable substances as for oral dosage formulations.

E. Evaluation of compound biological activity Standard physiological, pharmacological and biochemical studies of compounds to identify compounds with the physiological activity of endothelin peptides or the ability to interfere with or inhibit endothelin peptides Manual methods can be used. Compounds that exhibit in vitro activity, such as the ability to bind to or compete with one or more endothelin peptides for binding to the endothelin receptor, can be used to isolate endothelin receptors and to determine the specificity of the endothelin receptor. It can be used in a method of identification and is a candidate drug for use in a method of treating endothelin-mediated disorders.

  Thus, in addition to those specifically identified herein, other preferred compounds of Formulas I and II that are endothelin antagonists or agonists can be identified using such screening assays.

1. Confirmation of compounds that modulate the activity of endothelin peptide The ability of the compound to modulate the activity of endothelin-1 is examined. Many assays are known to those skilled in the art to assess the ability of a compound to modulate the activity of endothelin (eg, US Pat. No. 5,114,918 to Ishikawa et al .; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD ( (October 7, 1991); Borges et al . (1989) Eur. J. Pharm. , 165 : 223-230; Filep et al. (1991) Biochem. Biophys. Res.

Commun ., 177 : 171-176). In vitro testing can be confirmed by in vivo testing (see, eg, US Pat. No. 5,114,918 to Ishikawa et al; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (October 7, 1991)) thereby assessing the pharmacological activity. such assays, it has indicated in the examples herein, and to express either ET _a or ET _B on the cell surface by genetic manipulation It includes the ability to compete for binding to ET _a and ET _B present on membranes isolated from cell lines.

Antagonist candidate properties can be assessed as a function of the ability to inhibit in vitro- induced endothelin, using specific tissues such as rat portal vein and aorta and rat uterus, trachea and vas deferens (See, for example, Borges, R., Von Grafenstein, H. and Knight, DE, “Tissue selectivity of endothelin” Eur . J. Pharmacol ., 165 : 223-230 (1989)). The ability to act as an endothelin antagonist in vivo can be examined in hypertensive rats, ddy mice and other recognized animal models (Kaltenbronn et al . (1990) J. Med . Chem ., 33 : 838-845 See also; U.S. Pat. No. 5,114,918 to Ishikawa et al .; see also EP A1 0 436 189 (October 7, 1991) to BANYU PHARMACEUTICAL CO., LTD; further see Bolger et al . (1983) J. Pharmacol . Exp. .Ther. , 225 : 291-309). The results of such animal experiments can be used to assess pharmacological efficacy and to determine pharmaceutically effective formulations. Agent candidates can also be evaluated using in vitro and in vivo assays known to those skilled in the art.

Endothelin activity can be confirmed by the ability of the test compound to stimulate contraction of the isolated rat thoracic aorta (Borges et al . (1989) “Tissue selectivity of endothelin” Eur. J. Pharmacol ., 165 : 223-230). To perform the assay, the endothelium is exfoliated, and the annular section is attached in tension in a tissue bath and treated with endothelin in the presence of the test compound. Endothelin-induced tension changes are recorded. A dose response curve can be obtained and used to obtain data regarding the relative inhibitory potency of the test compound. Other tissues such as heart, skeletal muscle, uterus, trachea and vas deferens can be used to assess the effect of a particular test compound on tissue contraction.

Endothelin isotype-specific antagonists are based on the ability of a test compound to interfere with the binding of endothelin to various tissues or cells expressing various endothelin receptor subtypes or to interfere with the physiological effects of endothelin or endothelin isotypes. (Takayanagi et al ., (1991) Reg. Pep. , 32 : 23-37; Panek et al ., (1992) Biochem . Biophys . Res . Commun ., 183 : 566-571). For example, ET _B receptors are expressed in vascular endothelial cells, which may be mediated release of prostacyclin and endothelium-derived relaxing factor (De Nucci et al. (1988 ) Proc.Natl.Acad.Sci.USA, 85 : 9797). ET _A receptors are not detected in cultured endothelial cells that express ET _B receptors.

Binding or inhibition of binding of endothelin to the receptor of a compound to ET _B receptor by measuring the inhibition of endothelin-1-mediated release of prostacyclin, cultured bovine is that of stable major metabolite It can be evaluated by measurement with 6-keto PGF _1σ from aortic endothelial cells (see, for example, Filep et al . (1991) Biochem. And Biophys Res . Commun ., 177 : 171-176). Thus, the relative affinity of a compound for various endothelin receptors can be evaluated by obtaining an inhibitory dose-response curve using tissues with different receptor subtypes.

Using such assays, and to evaluate the relative affinity for ET _A receptors and ET _B receptors of the compounds, also it can be evaluated. Compounds having desirable properties such as specific inhibition of endothelin-1 binding are selected. Selected compounds that exhibit the desired activity may be therapeutically useful and are tested for such applications using the above assays that can be evaluated for in vivo efficacy (eg, US patents). U.S. Pat. No. 5,248,910; U.S. Pat. No. 5,198,548; U.S. Pat. No. 5,187,195; U.S. Pat. No. 5,082,838; U.S. Pat. 93/08799; Benigi et al . (1993) Kidney International , 44 : 440-444; and Nirei et al . (1993) Life Sciences 52 : 1869-1874). A compound exhibiting in vitro activity that correlates with in vivo efficacy is then formulated into a suitable pharmaceutical composition and used as a therapeutic agent.

  The compound may be used in methods of identifying and isolating endothelin-specific receptors, or even a compound that is a more potent endothelin antagonist or agonist or a compound that is more specific for a particular endothelin receptor Can be used to design

2. Isolation of endothelin receptor A method for confirming endothelin receptor is provided. In carrying out this method, one or more compounds are linked to a support and used in a method for affinity purification of the receptor. By selecting compounds with specific specificity, individual subclasses of ET receptors can be identified.

One or more compounds may be linked to such a suitable resin, either covalently or by other linkages, by methods known to those skilled in the art for linking endothelin to resins such as Affi-gel. (See Schvartz et al . (1990) Endocrinology , 126 : 3218-3222). The linked compound may be a compound specific for the ET _A or ET _B receptor or other receptor subclass.

The resin is pre-equilibrated with a suitable buffer, usually at physiological pH (7-8). A composition containing a solubilized receptor from a specific tissue is mixed with a compound-linked resin to selectively elute the receptor. Receptors can be identified by examining it for binding of endothelin to isopeptides or analogs, or by other methods of protein identification and characterization. Preparation of the receptor, resin and elution method can be done by modifying standard methods known to those skilled in the art (see, eg, Schvartz et al . (1990) Endocrinology , 126 : 3218-3222).

Other methods of identifying receptor types based on affinity differences for compounds of the invention are provided. The assays described herein for measuring affinity of specific compounds for endothelin receptors can also be used to identify receptor subclasses based on their affinity for specific compounds provided in the present invention. Specifically, an unknown receptor can be determined by measuring the binding affinity of an unknown receptor for a compound provided in the present invention for which the affinity of one receptor relative to the other receptor is known. It can be identified as an ET _A receptor or an ET _B receptor. Such preferential interactions are useful in determining specific diseases that can be treated with compounds produced according to the methods described herein. For example, it has high affinity for ET _A receptors, little affinity compounds without for ET _B receptors are candidates drug use as hypertensive agents. In contrast, preferentially compounds that interact with ET _B receptors are candidates drug use as anti-asthma agents.

  The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1
N- (4-Bromo-3-methyl-5-isoxazolyl) -2- (aminocarbonyl) thiophene-3-sulfonamidocarbonyldiimidazole (485 mg, 2.99 mmol) was added at room temperature to N- (4-bromo- 3-Methyl-5-isoxazolyl) -2-carboxylthiophene-3-sulfonamide (1 g, 2.72 mmol) was added to a THF (10 mL) solution. The mixture was stirred for 15 minutes. Aqueous NH ₃ (5 mL) was added and the mixture was stirred at room temperature for 30 minutes. Remove the solvent and remove the residue.

Partitioned between EtOAc and 1N HCl. The organic layer was dried (MgSO _4). The solid was filtered and the filtrate was concentrated. The oily residue was recrystallized from EtOAc to give N- (4-bromo-3-methyl-5-isoxazolyl) -2- (aminocarbonyl) thiophene-3-sulfonamide (946 mg, 95% yield) as a white solid Got as. Mp 168-170 ° C.

Example 2
N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(3,4-methylenedioxy) benzoyl] thiophene-3-sulfonamide
A. N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(N-methoxy-N-methyl) aminocarbonyl] thiophene-3-sulfonamide

  N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[((Similar to the method described in Example 1) except that N, O-dimethylhydroxylamine was used instead of ammonium hydroxide. N-methoxy-N-methyl) aminocarbonyl] thiophene-3-sulfonamide was prepared. The yield was 90%.

B. N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(3,4-methylenedioxy) benzoyl] thiophene-3-sulfonamide Freshly prepared (3,4-methylenedioxy) phenyl Magnesium bromide (1.28 g of (3,4-methylenedioxy) bromobenzene and 172 mg of chip-like Mg) was added at room temperature to N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(N- Methoxy-N-methyl) aminocarbonyl] thiophene-3-sulfonamide (A) (652 mg, 1.59 mmol) was added to a solution of THF (10 mL). The resulting mixture was refluxed for 30 minutes. As a workup, the mixture was cooled to room temperature and quenched with 1N HCl (10 mL). Next, THF was distilled off. The aqueous residue was partitioned between 1N HCl and EtOAc. The organic layer was concentrated and the residue was purified by HPLC to give N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(3,4-methylenedioxy) benzoyl] thiophene-3-sulfone. The amide (90 mg, 12% yield) was obtained as a dark yellow powder. Mp 47-49 ° C.

Example 3
N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(2-hydroxyphenyl) aminocarbonyl] thiophene-3-sulfonamide

  N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(2-hydroxy) was used in the same manner as in Example 1 except that 3-aminophenol was used instead of ammonium hydroxide. Phenyl) aminocarbonyl] thiophene-3-sulfonamide was prepared. The product was purified by HPLC to give N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(2-hydroxyphenyl) aminocarbonyl] thiophene-3-sulfonamide (50 mg, 18% yield). ) Was obtained as a dull yellow solid. Mp 42-44 ° C.

Example 4
N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(3,4-methylenedioxy) phenylacetyl] thiophene-3-sulfonamide (3,4-methylenedioxy) phenylmagnesium bromide Instead, N- (4-bromo-3-methyl-5 was used in the same manner as described in Example 2 except that piperonyl magnesium chloride was used and the reaction mixture was stirred overnight at room temperature without refluxing for 30 minutes. -Isoxazolyl) -2-[(3,4-methylenedioxy) phenylacetyl] thiophene-3-sulfonamide was prepared. The crude mixture was purified by HPLC to give N- (4-bromo-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) phenylacetyl] thiophene-3-sulfonamide (20 mg, yield). 40%) as a yellow oil.

Example 5
N- (4-Chloro-3-methyl-5-isoxazolyl) -2-[(3,4-methylenedioxy) phenylacetyl] thiophene-3-sulfonamide N- (4-bromo-3-methyl-5- Example 4 except that N- (4-chloro-3-methyl-5-isoxazolyl) -2-carboxylthiophene-3-sulfonamide was used instead of isoxazolyl) -2-carboxylthiophene-3-sulfonamide In a similar manner as described, N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(3,4-methylenedioxy) phenylacetyl] thiophene-3-sulfonamide was prepared. By HPLC purification, N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(3,4-methylenedioxy) phenylacetyl] thiophene-3-sulfonamide (3 g, 50% yield) was obtained. Obtained as a yellow solid. Mp 35-38 ° C.

Example 6
4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole and N- (4 -Chloro-3-methyl-5-isoxazolyl) -2- [2-methyl-4,5- (methylenedioxy) phenylacetyl] thiophene-3-sulfonamide, also referred to as N- (4-chloro-3- Methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methyl] phenylacetyl-3-thiophenesulfonamide
A. (3,4-methylenedioxy) -6-methylbenzyl chloride

To a 1: 1 mixture of ethyl ether (100 mL) and concentrated HCl (100 mL) was added (3,4-methylenedioxy) toluene (10 mL) at 0 ° C. Next, formaldehyde (20 mL, 37% aqueous solution) was added dropwise. The reaction was stirred at 0 ° C. for 2 hours and further stirred at room temperature for 10 hours. The reaction mixture was diluted with ethyl ether (100 mL) and the two layers were separated. The organic layer was dried (MgSO ₄ ), the solid was filtered and the filtrate was concentrated. The residue was heated with hexane (200 mL) and insoluble material was filtered off from the hot solution. The filtrate was concentrated to give (3,4-methylenedioxy) -6-methylbenzyl chloride (9.4 g, 63% yield) and bis [(3,4-methylenedioxy) -6-methyl] phenylmethane. A mixture of (3.6 g) was obtained as a white solid. This mixture was used in the next step without further purification.

B. N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methyl] phenylacetyl-3-thiophenesulfonamide (3,4-methylenedioxy) N- (4-Chloro-3-methyl-5-isoxazolyl) was used in the same manner as in Example 5 except that (3,4-methylenedioxy) -6-methylbenzyl chloride was used instead of benzyl chloride. ) -2- [3,4- (methylenedioxy) -6-methyl] phenylacetyl-3-thiophenesulfonamide was synthesized. The crude product was purified by preparative HPLC to give N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methyl] phenylacetyl-3- Thiophensulfonamide was obtained as a yellow powder (yield 71%, melting point 42-45 ° C.).

Example 7
4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole sodium salt
A. Preparation of 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole
Preparation of 1.5-chloromethyl-6-methylbenzo [d] [1,3] dioxole

  To a mixture of methylene chloride (130 liters), concentrated HCl (130 liters) and tetrabutylammonium bromide (1.61 kg) was added 5-methylbenzo [d] [1,3] dioxole (10 kg), followed by formaldehyde ( 14 liters, 37% aqueous solution) was slowly added dropwise. The mixture was stirred overnight. The organic layer was separated, dried over magnesium sulfate, and concentrated to give an oil. Hexane (180 liters) was added and the mixture was heated to boiling. The hot hexane solution was removed from the heavy oily residue by decantation and evaporated to give almost pure 5-chloromethyl-6-methylbenzo [d] [1,3] dioxole as a white solid. Recrystallization from hexane (50 liters) gave 5-chloromethyl-6-methylbenzo [d] [1,3] dioxole (80% recovery after recrystallization).

2. (4-Chloro-3-methyl-5- (2- (2- (2-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole Forming Magnesium Powder While stirring a slurry of (3.3 g, 0.136 g atom, Alfa or Johnson-Matthey, -20 + 100 mesh) in THF (120 mL), 5-chloromethyl-6-methylbenzo [d] [1,3] A portion of a solution of dioxole (16.8 g, 0.09 mol) in tetrahydrofuran was added at room temperature, and the resulting reaction mixture was allowed to warm to about 40-45 ° C. and allowed to elapse for about 2-3 minutes, allowing the reaction to proceed. When heating activated the magnesium and the reaction started, the mixture was cooled and the temperature was maintained below about 8 ° C. Instead of heating, dibromo By Tan, it may also activate the magnesium.

  The flask containing the reaction mixture was cooled, and the remaining 5-chloromethylbenzo [d] [1,3] dioxole solution was added dropwise over 1.5 hours while maintaining the internal temperature at 8 ° C. or lower. Temperature management is important. If a Grignard reagent is formed and the temperature is maintained at 8 ° C. or lower, Wurtz coupling does not occur. After a long time at a higher temperature, the Wurtzian coupling path is promoted. By using high quality Mg, maintaining the temperature of the Grignard reagent at about 8 ° C. or less and performing high stirring, it is possible to avoid wurtzite coupling. Since the reaction proceeds well at −20 ° C. or lower, a temperature of 8 ° C. or lower at which the Grignard reagent is generated is allowed. The color of the reaction mixture changes to greenish.

While the reaction mixture was stirred at 0 ° C. for an additional 5 minutes, N ² -methoxy-N ² -methyl-3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl) -2-thiophenecarboxamide (6 .6 g, 0.018 mol) in dehydrated THF (90 mL) was added via a dropping funnel. The reaction mixture was degassed twice and a solution of N ² -methoxy-N ² -methyl-3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl) -2-thiophenecarboxamide was added at 0 ° C. Over 5 minutes. TLC (silica, 12% MeOH / CH ₂ Cl ₂ ) of the reaction mixture taken immediately after addition showed N ² -methoxy-N ² -methyl-3- (4-chloro-3-methyl-5-isoxazolylsulfur). Famoyl) -2-thiophenecarboxamide was not shown.

The reaction mixture was washed with 1N HCl (400 mL, 0.4 mol).
HCl, stirred in an ice bath) and the mixture was stirred for 2-4 minutes, transferred to a separatory funnel and diluted with ethyl acetate (300 mL). After shaking, liquid separation was performed. The aqueous layer was extracted with additional ethyl acetate (150 mL) and the combined organic layers were washed with half brine. After liquid separation, the organic layer was dehydrated with sodium sulfate and concentrated under reduced pressure at about 39 ° C. to remove THF.

B. Preparation of 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole sodium salt The product from A above was redissolved in ethyl acetate and washed with saturated NaHCO ₃ (5 × 50 mL) until the wash became colorless. The solution was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a semi-crystalline yellow residue. To the solution was added 100 mL of CH ₂ Cl ₂ and the mixture was stirred under nitrogen for 5-10 minutes until a fine crystalline product was formed. Ether (150 mL) was added and the mixture was stirred for an appropriate time (eg, 10 minutes). The product was isolated by filtration, washed with a CH ₂ Cl ₂ / ether (1: 2) mixture (30 mL) and then ether (30 mL) and dried under reduced pressure. When prepared according to the above specific embodiment, the title compound was obtained in an amount of 7.3 g with a purity of about 85% (HPLC, RP, 40% acetonitrile / water, neutralized with ammonia, pH 2.5). 0.1% TFA, isocratic condition, 1 mL / min).

  The above salt product was dissolved in water (600 mL) at 10 ° C., the solution was stirred for a short time (eg, 3 minutes), and suction filtered through a filter paper layer (eg: 3 pieces of filter paper). In some cases, the filtration process becomes extremely slow due to the large amount of impurities (over 10%) that are not soluble in water. This problem can be avoided by using a relatively large filter during filtration. Usually, if the purity of the crude salt is 90% or more, there is no problem in filtration.

  The greenish and slightly turbid solution obtained from filtration was cooled in an ice bath and acidified to pH 2 with an acid such as 4N HCl. If the pH of the solution is 2, the product precipitates as a paste-like hard-to-filter material. By slow addition of excess 4N HCl slowly, the product gives a fine and easily filterable precipitate. The pale yellow precipitate was filtered, washed with water until neutral and pressed over filter paper to remove excess water. The free acid obtained usually had a purity of 95% as determined by HPLC.

The product free acid was dissolved in ethyl acetate (ca. 100 mL) and washed with brine (30 mL) to remove water. The dewatered solution was shaken with cold saturated NaHCO ₃ solution (2 × 30 mL), then again with brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure (bath temperature below 40 ° C.), very light yellow A foam was obtained. After complete removal of the ethyl acetate from the _product, CH ₂ Cl 2 to (100 mL) was added and the mixture was stirred for 5 to 10 minutes, to crystallize the product. Ether (150 mL) was added and stirring was continued for another 10 minutes. The resulting solid was isolated by filtration, washed with a mixture of CH ₂ Cl ₂ / ether (1: 2) (30 mL), then ether (30 mL), and dried under reduced pressure. After purification in this manner, 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamide was obtained. ) The isoxazole sodium salt was obtained in high yield (5.7 g, 68%) and high purity (98.2% purity by HPLC). If the initial purity is sufficiently high, the product can be further purified by recrystallization from EtOH / methyl t-butyl ether (MTBE) after the above procedure.

C. 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole sodium hydrogen phosphate N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methyl] phenylacetyl-3-thiophenesulfonamide, hydrogen phosphate, also referred to as salt Sodium salt N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methyl] phenylacetyl-3-thiophenesulfonamide (1.1492 g, 2. 5263 mmol) and disodium phosphate (0.3486 g, 2.5263 mmol) were added to deionized water (25 mL) and acetonitrile. Lil (25mL) was added. The resulting mixture was shaken well and heated at 50 ° C. to give a clear solution that was filtered. The filtrate was frozen at −78 ° C. and lyophilized to give the salt as a yellow powder (about 1.50 g).

Example 8
Formulation of sulfonamide salts as lyophilized powder
4-Chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole for parenteral administration -Preparation of sodium salt for injection (USP) A phosphate buffer was prepared by placing 3200 mL of sterile water in a 4-liter graduated cylinder. Disodium phosphate heptahydrate (USP, 21.44 g) was added to the sterile water and the mixture was stirred for 5 minutes, ie, until the solid dissolved. Monosodium phosphate (USP, 11.04 g) was added and the mixture was stirred until the solid dissolved. The solution was diluted to 4.0 liters and stirred. 3000 g of the above sodium phosphate buffer was placed in an 8 liter beaker. Glucose (USP, 200.0 g) was added and the mixture was heated to 30-35 ° C. in a water bath and stirred until a complete solution was obtained. 4-Chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamide with effective stirring ) Isoxazole sodium salt (100.0 g) was added. The mixture was stirred for a minimum of 10 minutes or until a solution was formed.

  After dissolving the sodium salt, the solution was removed from the water bath and diluted with sodium phosphate buffer to 4000 g and stirred for 5 minutes. This solution was aseptically filtered using a sterile 0.22 micron pre-size Durapore Millipak 2000 filter. The filtrate was filled into sterile vials and lyophilized under standard conditions. The vial was sealed. The lyophilized product was then regenerated with either 9.4 mL or 19.4 mL of water for injection to a final concentration of 25 mg / mL or 12.5 mg / mL, respectively.

Example 9
N- (4-Bromo-3-methyl-5-isoxazolyl) thiophene-2-sulfonamide 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) in dehydrated tetrahydrofuran (THF, 2 mL) Was added to a suspension of sodium hydride (60% mineral oil dispersion, 90 mg, 2.2 mmol) in dehydrated THF (1 mL) at 0-5 ° C. After stirring at 0-5 ° C. for 5 minutes, the reaction solution was stirred at room temperature for 10 minutes to complete the reaction. The reaction mixture was cooled again to 0 ° C., and a solution of thiophene-2-sulfonyl chloride (200 mg, 1.1 mmol) in dehydrated THF (2 mL) was added dropwise. Stirring was continued for 1 hour, during which time the reaction mixture was allowed to warm slowly to room temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 mL) and the pH was adjusted to 10-11 by adding 5N sodium hydroxide solution and extracted with ethyl acetate (3 × 10 mL) to remove neutral impurities. The aqueous layer was acidified with concentrated HCl (pH 2-3) and extracted with methylene chloride (3 × 10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N- (4-bromo-3-methyl-5-isoxazolyl) thiophene-2-sulfonamide. Pure product was obtained by recrystallization using hexane / ethyl acetate (110 mg, 34% yield). Mp 125-127 ° C.

Example 10
N- (4-Bromo-3-methyl-5-isoxazolyl) -5- (3-isoxazolyl) thiophene-2-sulfonamide

  A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) in dehydrated THF (2 mL) was added to sodium hydride (60% mineral oil dispersion, 90 mg, 2.2 mmol) in dehydrated THF (1 mL). ) Added to suspension at 0-5 ° C. After stirring at 0-5 ° C. for 5 minutes, the reaction solution was warmed to room temperature and allowed to pass for 10 minutes to complete the reaction. The reaction mixture was again cooled to 0 ° C., and a solution of 5- (3-isoxazolyl) thiophene-2-sulfonyl chloride (273 mg, 1.1 mmol) in dehydrated THF (2 mL) was slowly added dropwise. Stirring was continued for 1 hour, during which time the reaction mixture was allowed to warm slowly to room temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 mL) and the pH was adjusted to 2-3 by adding concentrated HCl and extracted with methylene chloride (3 × 10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N- (4-bromo-3-methyl-5-isoxazolyl) -5- (3-isoxazolyl) thiophene-2-sulfonamide. It was. Pure product was obtained by recrystallization using hexane / ethyl acetate (160 mg, 41% yield). Melting point 120-123 ° C.

Example 11
N- (4-bromo-3-methyl-5-isoxazolyl) -2- (carbomethoxy) thiophene-3-sulfonamide 5-amino-4-bromo-3-methylisoxazole and 2- (carbomethoxy) thiophene- The yield of N- (4-bromo-3-methyl-5-isoxazolyl) -2- (carbomethoxy) thiophene-3-sulfonamide was obtained from 3-sulfonyl chloride in the same manner as described in Example 10. % Manufactured. Purification by recrystallization from ethyl acetate / hexane gave a crystalline solid. Mp 198-200 ° C.

Example 12
N- (4-Bromo-3-methyl-5-isoxazolyl) -2- (carboxyl) thiophene-3-sulfonamide N- (4-Bromo-3-methyl-5-isoxazolyl) -2- (carbomethoxy) thiophene -3-sulfonamide (Example 11) (1.5 g, 3.95 mmol) was dissolved in methanol (10 mL). Sodium hydroxide pellets (1 g, 25 mmol) and a few drops of water were added. The resulting solution was stirred at room temperature for 16 hours. Methanol was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2 x 10 mL). The aqueous layer was acidified with concentrated hydrochloric acid (pH = 2) and extracted with ethyl acetate (2 × 60 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. Removal of the solvent gave N- (4-bromo-3-methyl-5-isoxazolyl) -2- (carboxymethoxy) thiophene-3-sulfonamide (1.2 g, 82% yield), which The eluent was purified by silica gel column chromatography using ethyl acetate. Mp 188-194 ° C.

Example 13
N- (3,4-dimethyl-5-isoxazolyl) -5-phenylthiophene-2-sulfonamide
A. N- (3,4-dimethyl-5-isoxazolyl) -5-bromothiophene-2-sulfonamide 5-bromothiophene-2-sulfonyl chloride (2.75 g, 10 mmol) and 5-amino-3,4-dimethyliso A pyridine solution containing 4-dimethylaminopyridine (DMAP, 10 mg) in a catalytic amount of oxazole (1.07 g, 9.57 mmol) was stirred at room temperature for 3 hours. The solution was heated at 50 ° C. for an additional 1.5 hours to accelerate the reaction and complete as judged by TLC. Pyridine is removed under reduced pressure and the residue is extracted with ethyl acetate, washed with 1N HCl (2 × 25 mL), water (1 × 25 mL), brine solution (1 × 25 mL), dried over magnesium sulfate did. Evaporation of the solvent gave a viscous brown gum that was flash chromatographed. Elution with 3% methanol / hexane gave 246 mg (10%) of pure sulfonamide.

B. N- (methoxyethoxymethyl) -N- (3,4-dimethyl-5-isoxazolyl) -5-bromothiophene-2-sulfonamide N- (3,4-dimethyl-5-isoxazolyl) -5-bromothiophene- A solution of 2-sulfonamide (680 mg, 2 mmol) in anhydrous THF (2 mL) was added to a suspension of sodium hydride (60% mineral oil dispersion 121 mg, 3 mmol) in anhydrous THF (1 mL). The resulting suspension was cooled to 0 ° C., and methoxyethoxymethyl chloride (334 mg, 2.68 mmol) was added dropwise with a syringe. The solution was warmed to room temperature and stirring was continued overnight. Solvent evaporation left an oil that was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated. The residue was flash chromatographed on silica gel with 15% ethyl acetate / hexane as eluent to give 480 mg (56%) of a colorless oil.

C. N- (methoxyethoxymethyl) -N- (3,4-dimethyl-5-isoxazolyl) -5-phenylthiophene-2-sulfonamide N- (methoxyethoxymethyl) -N- (3,4-dimethyl-5 To a solution of isoxazolyl) -5-bromothiophene-2-sulfonamide (200 mg, 0.47 mmol) and tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol) in dehydrated benzene (4 mL) under argon, Sodium carbonate (2 M aqueous solution 2 mL) was added followed by phenylboronic acid (86 mg, 0.71 mmol) in 95% ethanol (2 mL). The mixture was refluxed for 12 hours, diluted with 5 mL of water and extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were washed with brine (1 × 25 mL), dried and evaporated. The residue was flash chromatographed on silica gel with 25% ethyl acetate / hexane as eluent to give 123 mg (62%) of the sulfonamide as a colorless gum.

D. N- (3,4-dimethyl-5-isoxazolyl) -5-phenylthiophene-2-sulfonamide N- (methoxyethoxymethyl) -N- (3,4-dimethyl-5-isoxazolyl) -5-phenylthiophene- To a 95% ethanol (3 mL) solution of 2-sulfonamide (100 mg, 0.24 mmol) was added HCl (3N aqueous solution 3 mL) and the resulting mixture was refluxed for 6 hours. The mixture was concentrated, diluted with 5 mL of water, neutralized with saturated aqueous sodium bicarbonate and acidified to pH 4 using glacial acetic acid. The mixture was extracted with ethyl acetate (2 x 25 mL) and the combined organic extracts were washed with brine (1 x 5 mL), dried and evaporated. The residue was flash chromatographed on silica gel with 2% MeOH / CHCl _{3 as} eluent, and further reverse phase HPLC was performed to give 33.4 mg (42%) of pure sulfonamide as a white powder. Mp 176-178 ° C.

Example 14
N- (4-Bromo-3-methyl-5-isoxazolyl) -5- (4-ethylphenyl) thiophene-2-sulfonamide
A. N- (5-bromothiophene-2-sulfonyl) -pyrrole

  Sodium hydride (60% oil dispersion, 191 mg, 4.78 mmol) was suspended in dehydrated tetrahydrofuran (2 mL), and the resulting cloudy suspension was cooled to 0 ° C. in an ice bath. A solution of pyrrole (385 mg, 5.75 mmol) in dehydrated tetrahydrofuran (2 mL) was added dropwise over 10 minutes. The ice bath was removed and the solution was stirred at room temperature until gas evolution ceased (15 minutes). Therefore, 5-bromothiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) dissolved in tetrahydrofuran (4.0 mL) was added dropwise using a steel cannula. After stirring at room temperature for 1 hour, the mixture was filtered through Celite. The filtration layer was washed with tetrahydrofuran, and the filtrate was evaporated to leave a light brown solid. The solid was recrystallized from methanol to obtain sulfonamide (821 mg, yield 74%) as a white powder.

B. A solution of 4-ethylphenylboronic acid 1-bromo-4-ethylbenzene (2.0 g, 11 mmol) in dehydrated ether (5 mL) was added dropwise to chip-like magnesium (311 mg, 13 mmol) suspended in dehydrated ether. did. After completion of the dropwise addition, the suspension was refluxed for 15 minutes, during which almost all of the magnesium had reacted. The solution was added to a solution of trimethyl borate (1.12 g, 11 mmol) in ether (5 mL) at −78 ° C., warmed to room temperature, and stirred for 90 minutes. The reaction was quenched by the addition of 10% aqueous HCl (2 mL) and the solution was extracted with ether. The combined ether extracts were extracted with 1M NaOH (2 × 20 mL), the aqueous layer was acidified to pH 2 with dilute HCl and extracted with ether (2 × 25 mL). The resulting ether extracts were combined, washed once with water (10 mL), dried and evaporated to give a white solid (676 mg, 38% yield). Melting point: 138-140 ° C.

C. N- [5- (4-Ethylphenyl) thiophene-2-sulfonyl] pyrrole From 4-ethylphenylboronic acid and N- (5-bromothiophenesulfonyl) pyrrole in the same manner as described in Example 13C, N -[5- (4-Ethylphenyl) thiophene-2-sulfonyl] pyrrole was prepared. Purification by column chromatography using 10% ethyl acetate / hexanes afforded pure sulfonamide as a tan solid in 81% yield.

D. 5-chlorosulfonyl-2- (4-ethylphenyl) thiophene N- [5- (4-ethylphenyl) thiophene-2-sulfonyl] pyrrole (100 mg, 0.32 mmol) and 6N sodium hydroxide (1 mL) in methanol ( 1.5 mL) solution was refluxed for about 6 hours. Removal of the solvent and drying under reduced pressure gave an oil. Phosphorus oxychloride (258 mL, 2.52 mmol) and phosphorus pentachloride (131 mg, 0.63 mmol) were added to the oil and the resulting brown suspension was heated at 50 ° C. for 3 hours. The resulting clear brown solution was carefully added to about 20 mL of crushed ice and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (2 × 5 mL), dried (MgSO ₄ ) and evaporated to give an oily residue. Flash chromatography on silica gel with 2% ethyl acetate / hexanes afforded pure sulfonyl chloride as a pale yellow oil (53 mg, 59%).

E. N- (4-Bromo-3-methyl-5-isoxazolyl) -5- (4-ethylphenyl) thiophene-2-sulfonamide N- (4-Bromo-3) was prepared in the same manner as described in Example 10. -Methyl-5-isoxazolyl) -5- (4-ethylphenyl) thiophene-2-sulfonamide was prepared. Reaction of 5-chlorosulfonyl-2- (4-ethylphenyl) thiophene (47.1 mg, 11.16 mmol) with 5-amino-4-bromo-3-methylisoxazole (29 mg, 0.16 mmol) gave 10 After flash chromatography using% MeOH / CHCl ₃ , a light brown solid was obtained (46 mg, 66% yield). Mp 172-175 ° C.

Example 15
From N- (4-bromo-3-methyl-5-isoxazolyl) -4-phenethylthiophene-2-sulfonamide 5-amino-4-bromo-3-methylisoxazole and 4-phenethyl-2-thiophenesulfonyl chloride, In the same manner as described in Example 10, N- (4-bromo-3-methyl-5-isoxazolyl) -4-phenethylthiophene-2-sulfonamide was produced in a yield of 32%. This was purified by HPLC (5% CH ₃ CN to 100% CH ₃ CN over 30 minutes) to give a gum.

Example 16
N- (4-Bromo-3-methyl-5-isoxazolyl) -2- [N- (3-carboxyphenylaminocarbonyl] thiophene-3-sulfonamide Et ₃ N (2.27 mL, 16. mmol), 3- Ethyl aminobenzoate (836 mL, 5.44 mmol) and phosphonitrile chloride trimer (1.89 g, 5.44 mmol) in that order, N- (4-bromo-3-methyl-5-isoxazolyl) -2 -(Carbonyl) thiophene-3-sulfonamide (Example 12) (1 g, 2.27 mmol) was added to a solution of dehydrated THF (20 mL) The reaction was stirred at room temperature for 1 h and cooled. The resulting solution was concentrated on a rotary evaporator and the residue was diluted with EtOAc and washed with 2N HCl. (2 x 150 mL). The organic layer was dried (MgSO _4). The solid was filtered off, the filtrate was concentrated. The residue was treated with 1N NaOH (200 mL), was stirred for 15 min at 0 ° C.. The mixture Acidify with concentrated HCl to pH about 1. The resulting yellow precipitate is filtered and recrystallized from CH ₃ CN / H ₂ O to give N- (4-bromo-3-methyl-5-isoxazolyl)- 2- [N- (3-carboxyphenyl) aminocarbonyl] thiophene-3-sulfonamide (153 mg, 11.6%) was obtained as a yellowish powder, mp 183-185 ° C.

Example 17
N- (4-Bromo-5-methyl-3-isoxazolyl) -5- (4-methylphenyl) thiophene-2-sulfonamide
A. N- [5- (4-Methylphenyl) thiophene-2-sulfonyl] pyrrole Similar to the method described in Example 13C using 4-methyl-phenylboronic acid and N- (5-bromothiophenesulfonyl) pyrrole. Thus, N- [5- (4-methylphenyl) thiophene-2-sulfonyl] pyrrole was produced. Purification by column chromatography using 2% ethyl acetate / hexanes gave N- [5- (4-methylphenyl) thiophene-2-sulfonyl] pyrrole as a pale yellow solid in 77% yield.

B. 2-Chlorosulfonyl-5- (4-methylphenyl) thiophene N- [5- (4-methylphenyl) thiophene-2-sulfonyl] pyrrole was used in the same manner as described in Example 14D to produce 2- Chlorosulfonyl-5- (4-methylphenyl) thiophene was prepared. Purification by column chromatography using 2% ethyl acetate / hexane gave 2-chlorosulfonyl-5- (4-methylphenyl) thiophene as a pale yellow powder (61% yield).

C. N- (4-Bromo-3-methyl-5-isoxazolyl) -5- (4-methylphenyl) thiophene-2-sulfonamide In analogy to the method described in Example 10, N- (4-Bromo-3 -Methyl-5-isoxazolyl) -5- (4-methylphenyl) thiophene-2-sulfonamide was prepared. Reaction of 2-chlorosulfonyl-5- (4-methylphenyl) thiophene (100 mg, 0.37 mmol) with 5-amino-4-bromo-3-methylisoxazole (65 mg, 0.37 mmol) gave 10% MeOH. After column chromatography using / CHCl ₃ , 96 mg of the final product was obtained as a pale yellow solid (yield 63%, melting point 175 ° C.).

Example 18
N- (4-Bromo-3-methyl-5-isoxazolyl) -5- (benzyloxymethyl) thiophene-2-sulfonamide
A. Sodium 2- (benzyloxymethyl) thiophene hydride (0.41 mg, 20 mmol) was added to a solution of 2-thiophenemethanol (2.0 g, 0.18 mmol) in THF (20 mL) at −40 ° C. The reaction was stirred at −40 ° C. for 25 minutes and undiluted benzyl bromide (3.6 g, 20 mmol) was added via syringe. The solution was stirred at −40 ° C. for 0.5 hour and then stirred at room temperature for 1 hour. The THF was distilled off and the resulting residue was taken up in ether (ca. 50 mL). The organic solution was washed with water (1 × 10 mL), brine (1 × 10 mL) and dried over MgSO ₄ . Evaporation of the solvent gave an oil that was purified by column chromatography using 1% ether-hexane to give 2.6 g of the thiophene as a pale yellow oil (yield 78%).

B. 2-Chlorosulfonyl-5- (benzyloxymethyl) thiophene From 2- (benzyloxymethyl) thiophene (1.0 g, 5.25 mmol) in a similar manner as described in Example 17A, 2-chlorosulfonyl-5 -(Benzyloxymethyl) thiophene was prepared. Purification by column chromatography using 2.5% ethyl acetate / hexanes afforded 520 mg of the pure thiophene as a brown oil (yield 32%).

C. N- (4-bromo-3-methyl-5-isoxazolyl) -5- (benzyloxymethyl) thiophene-2-sulfonamide 2-chlorosulfonyl-5- (benzyloxymethyl) thiophene (520 mg, 1.72 mmol) and From 5-amino-4-bromo-3-methylisoxazole (319 mg, 1.8 mmol) according to the method described in Example 10, N- (4-bromo-3-methyl-5-isoxazolyl) -5- ( (Benzyloxymethyl) thiophene-2-sulfonamide was prepared. Column chromatography purification using 10% MeOH / CHCl ₃ gave 238 mg of pure N- (4-bromo-3-methyl-5-isoxazolyl) -5- (benzyloxymethyl) thiophene-2-sulfonamide as brown half Obtained as a solid (yield 31%, melting point 92 ° C.).

Example 19
N- (4-Bromo-3-methyl-5-isoxazolyl) -3- [3,4- (methylenedioxy) phenyl] thiophene-2-sulfonamide
A. 3- Bromothiophene- 2-sulfonyl chloride chlorosulfonic acid (20 mL, 300 mmol) was added to a solution of 3-bromothiophene (8.15 g, 50 mmol) in methylene chloride (50 mL) at −78 ° C. over 20 minutes. After the addition was complete, the cooling bath was removed and stirring was continued for 1 hour at room temperature. The reaction mixture was carefully added dropwise to crushed ice (100 g). The mixture was extracted with methylene chloride (2 x 100 mL). The combined organic layers were dried over MgSO ₄ and evaporated. The crude product was purified by flash chromatography on silica gel using hexane as eluent to give 3-bromothiophene-2-sulfonyl chloride (4 g, 30% yield) and 4-bromothiophene-2-sulfonyl chloride ( 200 mg, ≦ 1%) was obtained.

B. N- (3-Bromothiophene-2-sulfonyl) pyrrole By reacting 3-bromothiophene-2-sulfonyl chloride with pyrrole (16 hours), in the same manner as described in Example 14A, N- ( 3-Bromothiophene-2-sulfonyl) pyrrole was prepared. N- (3-bromothiophene-2-sulfonyl) pyrrole was obtained with a yield of 54%.

C. Using N-{[3- (3,4-methylenedioxy) phenyl] thiophene-2-sulfonyl} pyrrole 3,4-methylenedioxyphenylboronic acid and N- (3-bromothiophene-2-sulfonyl) pyrrole In the same manner as in Example 13C, N-{[3- (3,4-methylenedioxy) phenyl] thiophene-2-sulfonyl} pyrrole was produced. The crude product was purified by flash column chromatography on silica gel using 2% EtOAc as eluent to give N-{[3- (3,4-methylenedioxy) phenyl] thiophene-2-sulfonyl} pyrrole. The yield was 90%.

D. 2-Chlorosulfonyl-3- [3,4- (methylenedioxy) phenyl] thiophenesulfonamide is converted to the sulfonic acid sodium salt by basic hydrolysis (yield 100%), followed by the corresponding sulfonyl chloride Into 2-chlorosulfonyl using N-{[3- (3,4-methylenedioxy) phenyl] thiophene-2-sulfonyl} pyrrole in the same manner as described in Example 18B. -3- [3,4- (Methylenedioxy) phenyl] thiophene was prepared and the final product was obtained in 34% yield.

E. N-(4-bromo-3-methyl-5-isoxazolyl) -3- [3,4- (methylenedioxy) phenyl] thiophene-2-sulfonamide 2-chlorosulfonyl-3- [3,4- (methylene Di-oxy) phenyl] thiophene and 5-amino-4-bromo-3-methylisoxazole were reacted in the same manner as described in Example 9 with N- (4-bromo-3-methyl-5- Isoxazolyl) -3- [3,4- (methylenedioxy) phenyl] thiophene-2-sulfonamide was produced, and the yield was 60%. Mp 183-186 ° C.

Example 20
N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(2-chloro-3,4-methylenedioxy) phenoxymethyl] thiophene-3-sulfonamide
A. A solution of N- {2-[(3,4-methylenedioxy) phenoxymethyl] thiophene-3-sulfonyl} pyrrole 3,4-methylenedioxyphenol (0.607 g, 4.5 mmol) in DMF (dehydrated, 5 mL) Was brought to 0 ° C. under nitrogen and sodium hydride (100 mg, 5 mmol) was added with stirring. The reaction mixture was warmed to room temperature and stirring was continued for 1 hour. The reaction mixture was cooled to 0 ° C. and N-[(2-bromomethyl) thiophene-3-sulfonyl] pyrrole was added. Stirring was continued for 16 hours at room temperature. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2 × 50 mL), washed with 1N NaOH (2 × 25 mL) to remove the phenol derivative. The mixture was dried over MgSO ₄ and concentrated to give N- {2-[(3,4-methylenedioxy) phenoxymethyl] thiophene-3-sulfonyl} pyrrole. It was recrystallized using hexane / EtOAc (1.0 g, 92% yield).

B. 3-Chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxy) phenoxymethyl] thiophene basic hydrolysis (using potassium hydroxide in isopropanol) to the sulfonic acid potassium salt, followed by Similar to the method described in Example 15E using N- {2-[(3,4-methylenedioxy) phenoxymethyl] thiophene-3-sulfonyl} pyrrole by converting the salt to the corresponding sulfonyl chloride. Thus, 3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxy) phenoxymethyl] thiophene was produced in a yield of 50%.

C. N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(2-chloro-3,4-methylenedioxy) phenoxymethyl] thiophene-3-sulfonamido 3-chlorosulfonyl-2-[( 2-chloro-3,4-methylenedioxyphenoxy) methyl] thiophene is reacted with 5-amino-4-bromo-3-methylisoxazole in a manner similar to that described in Example 9 to produce N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(2-chloro-3,4-methylenedioxyphenoxy) methyl] thiophene-3-sulfonamide was prepared in 47% yield. Mp 152-154 ° C.

Example 21
N- (4-Bromo-3-methyl-5-isoxazolyl) -2- [trans-3,4- (methylenedioxy) cinnamyl] thiophene-3-sulfonamide
A. 2- {3-[(N-pyrrole) sulfonyl] thienylmethyl} diethyl N- [2-bromomethyl) thiophene-3-sulfonyl] pyrrole (0.915 g, 3 mmol) was added to triethyl phosphite (5 mL). Suspended and stirred at 140 ° C. for 1 hour with stirring under nitrogen. Excess triethyl phosphite was removed under reduced pressure, and the residue was dried under reduced pressure to give 0.9 g (83% yield) of 2- {3-[(N-pyrrole) sulfonyl] thienylmethyl} phosphate. Obtained.

B. N- {2- [trans-3,4- (methylenedioxy) cinnamyl] thiophene-3-sulfonyl} pyrrole 2- {3-[(N-pyrrole) sulfonyl] thienylmethyl} diethyl phosphate (900 mg, 2. 48 mmol) in dehydrated THF (10 mL) was stirred at 0 ° C., and sodium hydride (200 mg, 60% dispersion) was added in two portions. The mixture was stirred at room temperature for 1 hour and piperonal (600 mg) was added. Stirring was continued for 12 hours. The mixture was diluted with water (100 mL) and extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried over MgSO ₄ and the residue was subjected to flash chromatography on silica gel with 0.5% ethyl acetate / hexane to give N- {2- [trans-3,4- (methylenedi Oxy) cinnamyl] thiophene-3-sulfonyl} pyrrole (750 mg, 84% yield) was obtained.

C. 3-Chlorosulfonyl-2- [trans-3,4- (methylenedioxy) cinnamyl] thiophene basic hydrolysis (using potassium hydroxide and isopropanol) to the corresponding sulfonic acid potassium salt (100%), followed by And converting the salt to the corresponding sulfonyl chloride using N- {2- [trans-3,4- (methylenedioxy) cinnamyl] thiophene-3-sulfonyl} pyrrole as described in Example 15E. In the same manner as in the method, 3-chlorosulfonyl-2- [trans-3,4- (methylenedioxy) cinnamyl] thiophene was produced in a yield of 31%.

D. N- (4-Bromo-3-methyl-5-isoxazolyl) -2- [trans-3,4- (methylenedioxy) cinnamyl] thiophene-3-sulfonamido 3-chlorosulfonyl-2- [trans-3, 4- (methylenedioxy) cinnamyl] thiophene and 5-amino-4-bromo-3-methylisoxazole were reacted in the same manner as described in Example 9 with N- (4-bromo-3- Methyl-5-isoxazolyl) -2- [trans-3,4- (methylenedioxy) cinnamyl] thiophene-3-sulfonamide was prepared. The crude product was purified by HPLC to give a yield of 33%. Mp 147-149 ° C.

Example 22
N- (4-Bromo-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) phenethyl] thiophene-3-sulfonamide
A. N- {2- [3,4- (methylenedioxy) phenethyl] thiophene-3-sulfonyl} pyrrole N- {2- [trans-3,4- (methylenedioxy) cinnamyl] thiophene-3-sulfonyl} pyrrole A solution of (Example 21B, 0.6 g, 1.67 mmol) in ethyl acetate (15 mL) was catalytically hydrogenated using 10% Pd—C (100 mg) at 55 psi for 14 hours. The catalyst was filtered and the filtrate was concentrated to give N- {2- [3,4- (methylenedioxy) phenethyl] thiophene-3-sulfonyl} pyrrole (0.55 g, 91% yield).

B. Basic hydrolysis of 3-chlorosulfonyl-2- [3,4- (methylenedioxy) phenethyl] thiophenesulfonamide (isopropanol and potassium hydroxide) to give the potassium salt of sulfonic acid (93%), followed by And converting the salt to the corresponding sulfonyl chloride using N- {2- [3,4- (methylenedioxy) phenethyl] thiophene-3-sulfonyl} pyrrole and the method described in Example 15E Similarly, 3-chlorosulfonyl-2- [3,4- (methylenedioxy) phenethyl] thiophene was produced in a yield of 42%.

C. N- (4-Bromo-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) phenethyl] thiophene-3-sulfonamide In the same manner as described in Example 10, N- (4-Bromo-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) phenethyl] thiophene-3-sulfonamide was prepared. 3-Chlorosulfonyl-2- [3,4- (methylenedioxy) phenethyl] thiophene is reacted with 5-amino-4-bromo-3-methylisoxazole and the crude product is purified by HPLC to give N -(4-Bromo-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) phenethyl] thiophene-3-sulfonamide was obtained in a yield of 30%. Melting point 180 ° C. (decomposition).

Example 23
N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(4-methyl) (cinnamyl)] thiophene-3-sulfonamide
A. Example using N- [2- (4-methyl-trans-styryl) -3-sulfonyl} pyrrole {3- (N-pyrrolylsulfonyl) thien-2- [yl] methylphosphonate and 4-methylbenzaldehyde N- [2- (4-Methyl-trans-styryl) -3-sulfonyl} pyrrole was produced in a yield of 30% in the same manner as described in 21B.

B. 2- (4-methyl-trans-styryl) thiophene-3-sulfonyl chloride converted to the corresponding sodium sulfonate by basic hydrolysis (using ethanol and sodium hydroxide) and then converted to the corresponding sulfonyl chloride, N 2- (4-Methyl-trans-styryl) thiophene from-[2- (4-methyl-trans-styryl) -3-sulfonyl} pyrrole in a similar manner as described in Example 15E in 13% yield. -3-Sulphonyl chloride was produced.

C. N- (4-Bromo-3-methyl-5-isoxazolyl) -2- (4-methyl-trans-styryl) thiophene-3-sulfonamide 2- (4-methyl-trans-styryl) thiophene-3-sulfonyl chloride N- (4-Bromo-3-methyl-5-isoxazolyl) -2- (2) in the same manner as described in Example 10 by reacting with 5-amino-4-bromo-3-methylisoxazole. 4-Methyl-trans-styryl) thiophene-3-sulfonamide was prepared. The crude product was purified by HPLC and crystallized to obtain a yield of 34%. Melting point 101-105 ° C.

Example 24
N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(4-methyl) phenethyl] thiophene-3-sulfonamide
A. N- {2-[(4-methyl) phenethyl] thiophene- 3-sulfonyl} pyrrole Catalytic hydrogenation of N- [2- (4-methyl-trans-styryl) -3-sulfonyl} pyrrole provides Example 22A. In the same manner as described, N- {2-[(4-methyl) phenethyl] thiophene-3-sulfonyl} pyrrole was produced in 80% yield.

B. Obtaining its potassium salt by basic hydrolysis (KOH / ethanol) of 2-[(4-methyl) phenethyl] thiophene-3-sulfonyl chloride sulfonamide, and then converting the salt to the corresponding sulfonyl chloride In the same manner as described in Example 15E using N- {2-[(4-methyl) phenethyl] thiophene-3-sulfonyl} pyrrole, 2-[(4-methyl) phenethyl] thiophene- 3-sulfonyl chloride was prepared in 51% yield.

C. N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(4-methyl) phenethyl] thiophene-3-sulfonamide 2-[(4-methyl) phenethyl] thiophene-3-sulfonyl chloride and 5 N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(4-methyl) phenethyl according to the method described in Example 10 using -amino-4-bromo-3-methylisoxazole Thiophene-3-sulfonamide was prepared in 52% yield.

Example 25
N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(4-methylphenoxy) methyl] thiophene-3-sulfonamide
A. N- {2-[(4-methylphenoxy) methyl] thiophene-3-sulfonyl} pyrrole

  N- {2-[(4-methylphenoxy) methyl] thiophene- is reacted according to the method described in Example 20A by reacting N- [2-bromomethyl) thiophene-3-sulfonyl] pyrrole with 4-methylphenol. 3-sulfonyl} pyrrole was produced in 81% yield.

B. 2-[(4-Methylphenoxy) methyl] thiophene-3-sulfonyl chloride basic hydrolysis (NaOH / EtOH) followed by conversion to the corresponding sulfonyl chloride resulted in N- {2-[(4-methylphenoxy). 2-[(4-Methylphenoxy) methyl] thiophene-3-sulfonyl chloride was prepared in 46% yield according to the method described in Example 15E using) methyl] thiophene-3-sulfonyl} pyrrole.

C. N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(4-methylphenoxy) methyl] thiophene-3-sulfonamide 2-[(4-methylphenoxy) methyl] thiophene-3-sulfonyl chloride Is reacted with 5-amino-4-bromo-3-methylisoxazole according to the method described in Example 10 and N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(4 -Methylphenoxy) methyl] thiophene-3-sulfonamide was prepared in 64% yield. Melting point 128-130 ° C.

Example 26
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methyl] phenylaminocarbonyl-3-thiophenesulfonamide
A. A solution of (3,4-methylenedioxy ) -6-methylaniline (3,4-methylenedioxy) toluene (5 mL) in acetic acid (20 mL) was cooled in an ice-water bath, and nitric acid (70%, 5 mL) was added dropwise thereto. did. The mixture was stirred for 45 minutes. As a workup, water (100 mL) was added and the resulting yellow precipitate was filtered and washed with water until the filtrate water was colorless. The yellow solid was dissolved in EtOAc (250 mL), dried (MgSO ₄ ) and the solid was filtered off. The filtrate was subjected to catalytic hydrogenation (10% Pd / C, 1 atm) for 12 hours. The catalyst was filtered off from the reaction mixture, and the filtrate was concentrated on a rotary evaporator to give (3,4-methylenedioxy) -6-methylaniline as a brownish gray solid (5.49 g, 87% yield). .

B. N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methyl] phenylaminocarbonyl-3-thiophenesulfonamide (3,4-methylenedioxy ) -6-methylaniline in the same manner as described in Example 3, N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-Methyl] phenylaminocarbonyl-3-thiophenesulfonamide was synthesized. The crude product was purified by preparative HPLC to give N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methyl] phenylaminocarbonyl-3. -Thiophensulfonamide was obtained as a yellow solid (45% yield, melting point 60-62%).

Example 27
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- (3-methoxycarbonyl-2,4,6-trimethyl) phenylaminocarbonyl-3-thiophenesulfonamide
A. In the same manner as methyl 3-amino-2,4,6-trimethylbenzoate (3,4-methylenedioxy) -6-methylaniline, methyl 3-amino-2,4,6-trimethylbenzoate was prepared. Synthesized (see Example 26).

B. N- (4-Chloro-3-methyl-5-isoxazolyl) -2- (3-methoxycarbonyl-2,4,6-trimethyl) phenylaminocarbonyl-3-thiophenesulfonamide Reaction using DMF instead of THF N- (4-Chloro-3-methyl-5-isoxazolyl) -2- (3-methoxycarbonyl-2,4) was prepared in the same manner as described in Example 3 except that the solution was stirred at 80 ° C. for 5 hours. , 6-Trimethyl) phenylaminocarbonyl-3-thiophenesulfonamide was synthesized. The crude product was purified by preparative HPLC to give N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-methoxycarbonyl-2,4,6-trimethyl) phenylaminocarbonyl-3- Thiophensulfonamide was obtained as an off-white powder (48 mg, 1% yield, melting point 66-70 ° C.).

Example 28
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl) phenylacetyl-3-thiophenesulfonamide 2,4,6-trimethylbenzyl chloride and N- (4- Chloro-3-methyl-5-isoxazolyl) -2- (N-methyl-N′-methoxy) aminocarbonyl-3-thiophenesulfonamide was used in the same manner as described in Example 5 for N- ( 4-Chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl) phenylacetyl-3-thiophenesulfonamide was synthesized. The crude product was purified by flash chromatography (eluent 1% methanol / CH ₂ Cl ₂ ) to give N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl). ) Phenylacetyl-3-thiophenesulfonamide was obtained as a solid (yield 31%, melting point 42-46 ° C.).

Example 29
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl) phenylaminocarbonyl-3-thiophenesulfonamide In the same manner as described in Example 3, N- (4-Chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl) phenylaminocarbonyl-3-thiophenesulfonamide was synthesized. The crude product was purified by preparative HPLC to yield N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4,6-trimethyl) phenylaminocarbonyl-3-thiophenesulfonamide. Like-brown powder (410 mg, 30% yield, melting point 45-48 ° C.).
Example 30
N- (3,4-dimethyl-5-isoxazolyl) -2- (2,4-dimethyl) phenylacetyl-3-thiophenesulfonamide

Example 5 was prepared using 2,4-dimethylbenzyl chloride and N- (3,4-dimethyl-5-isoxazolyl) -2- (N-methyl-N′-methoxy) aminocarbonyl-3-thiophenesulfonamide. N- (3,4-dimethyl-5-isoxazolyl) -2- (2,4-dimethyl) phenylacetyl-3-thiophenesulfonamide was synthesized by the same method as described. The crude product was purified by flash column chromatography (eluent 1% methanol / CH ₂ Cl ₂ ) and further by preparative HPLC to give N- (3,4-dimethyl-5-isoxazolyl) -2- (2,4 -Dimethyl) phenylacetyl-3-thiophenesulfonamide was obtained as a semi-solid (yield 34%).

Example 31
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4-dimethyl) phenylacetyl-3-thiophenesulfonamide 2,4-dimethylbenzyl chloride and N- (4-chloro-3- Methyl-5-isoxazolyl) -2- (N-methyl-N′-methoxy) aminocarbonyl-3-thiophenesulfonamide was used in a manner similar to that described in Example 5 to give N- (4-chloro -3-Methyl-5-isoxazolyl) -2- (2,4-dimethyl) phenylacetyl-3-thiophenesulfonamide was synthesized. The crude product was purified by flash column chromatography (eluent 1% methanol / CH ₂ Cl ₂ ) to give N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,4-dimethyl). Phenylacetyl-3-thiophenesulfonamide was obtained as a solid (yield 52%, melting point 48-54 ° C.).

Example 32
N- (4-Bromo-3-methyl-5-isoxazolyl) -2- (2,4-dimethyl) phenylacetyl-3-thiophenesulfonamide 2,4-dimethylbenzyl chloride and N- (4-bromo-3- Methyl-5-isoxazolyl) -2- (N-methyl-N′-methoxy) aminocarbonyl-3-thiophenesulfonamide was used in a manner similar to that described in Example 5 to give N- (4-bromo -3-Methyl-5-isoxazolyl) -2- (2,4-dimethyl) phenylacetyl-3-thiophenesulfonamide was synthesized. The crude product was purified by flash column chromatography (eluent 1% methanol / CH ₂ Cl ₂ ) and further by preparative HPLC to give N- (4-bromo-3-methyl-5-isoxazolyl) -2- (2 , 4-Dimethyl) phenylacetyl-3-thiophenesulfonamide was obtained as a solid (yield 28%, melting point 63 ° C.).

Example 33
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3,5-dimethyl) phenylacetyl-3-thiophenesulfonamide 3,5-dimethylbenzyl bromide and N- (4-chloro-3- Methyl-5-isoxazolyl) -2- (N-methyl-N′-methoxy) aminocarbonyl-3-thiophenesulfonamide was used in a manner similar to that described in Example 5 to give N- (4-chloro -3-Methyl-5-isoxazolyl) -2- (3,5-dimethyl) phenylacetyl-3-thiophenesulfonamide was synthesized. The crude product was purified by flash column chromatography (eluent 2% methanol / CH ₂ Cl ₂ ) to give N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3,5-dimethyl). Phenylacetyl-3-thiophenesulfonamide was obtained as a solid (yield 57%, melting point 45-50 ° C.).

Example 34
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- (2,5-dimethyl) phenylacetyl-3-thiophenesulfonamide 2,5-dimethylbenzyl chloride and N- (4-chloro-3- Methyl-5-isoxazolyl) -2- (N-methyl-N′-methoxy) aminocarbonyl-3-thiophenesulfonamide was used in a manner similar to that described in Example 5 to give N- (4-chloro -3-Methyl-5-isoxazolyl) -2- (2,5-dimethyl) phenylacetyl-3-thiophenesulfonamide was synthesized. The crude product was purified by flash column chromatography (eluent 2% methanol / CH ₂ Cl ₂ ) to give N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,5-dimethyl). Phenylacetyl-3-thiophenesulfonamide was obtained as a solid (yield 33%, melting point 72-76 ° C.).

Example 35
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6- (2-acetoxyethyl)] phenylaminocarbonyl-3-thiophenesulfonamide
A. A solution of 2- (3,4-methylenedioxy) phenyl-1-ethanol 2- (3,4-methylenedioxy) phenylacetic acid (5 g, 25.75 mmol) in dehydrated THF (20 mL) was brought to 0 ° C. and BH ₃ · THF was added (40 mL, THF solution of 1.0 M). The mixture was stirred at room temperature for 1 hour. As a post-treatment, THF was distilled off with a rotary evaporator. The residue was treated with water (100 mL), acidified and extracted with ether (2 × 100 mL). The solvent was removed under reduced pressure to give 2- (3,4-methylenedioxy) phenyl-1-ethanol as an oil (4.7 g, 98% yield).

B. Stir a dehydrated pyridine solution of 1-acetoxy-2-[(3,4-methylenedioxy) phenyl] ethane 2- (3,4-methylenedioxy) phenyl-1-ethanol (1.68 g, 10 mmol), Acetic anhydride was added thereto, and the resulting reaction mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was poured into ice water and extracted with ether (2 x 75 mL). The combined ether extracts were washed with water (2 × 50 mL), 5% HCl (2 × 50 mL) and NaHCO ₃ (2 × 50 mL). The organic layer was dehydrated with magnesium sulfate and the solvent was removed under reduced pressure to give 1-acetoxy-2-[(3,4-methylenedioxy) phenyl] ethane as a solid (1.7 g, yield 81). %).

C. 1-acetoxy-2-[(3,4-methylenedioxy) -6-nitrophenyl] ethane 1-acetoxy-2-[(3,4-methylenedioxy) phenyl] ethane (1.7 g, 8.09 mmol) Concentrated HNO ₃ (4.5 mL) was added dropwise to a stirred solution of acetic acid (10 mL). It was stirred for 30 minutes at room temperature. The reaction mixture was poured into water (100 mL). The precipitated solid was filtered, washed with water and dried under high vacuum to give 1-acetoxy-2-[(3,4-methylenedioxy) -6-nitrophenyl] ethane (1.8 g, Yield 88%).

D. 1-acetoxy-2-[(3,4-methylenedioxy) -6-aminophenyl] ethane 1-acetoxy-2-[(3,4-methylenedioxy) -6-nitrophenyl] ethane (0.8 g 3.13 mmol) in ethyl acetate (25 mL) was subjected to catalytic hydrogenation with 10% palladium on carbon (100 mg) at 50 psi for 30 minutes. The catalyst was filtered off and the solvent removed under reduced pressure to give 1-acetoxy-2-[(3,4-methylenedioxy) -6-aminophenyl] ethane as a solid (0.69 g, yield). 98%).

E. N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6- (2-acetoxyethyl)] phenylaminocarbonyl-3-thiophenesulfonamide Example 16 N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6- (2-acetoxyethyl)] phenylaminocarbonyl-3- Thiophenesulfonamide was synthesized. The crude product was purified by preparative HPLC to give N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6- (2-acetoxyethyl)]. Phenylaminocarbonyl-3-thiophenesulfonamide was obtained as a dull yellow powder (yield 12%, melting point 78-82 ° C.).

Example 36
Other compounds prepared by the above methods or conventional variations of those methods include, but are not limited to: That is, N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(4-methoxyphenoxy) carbonyl] thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) ) -2-[(4-Methylphenoxy) carbonyl] thiophene-3-sulfonamide; N- (4-Bromo-3-methyl-5-isoxazolyl) -3-[(4-methylphenoxy) methyl] thiophene-2 -Sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(4-methylphenoxy) methyl] thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5 -Isoxazolyl) -3- (4-methyl-trans-styryl) thiophene-2-sulfonamide; N- (4-bromo-3-methy -5-isoxazolyl) -3- (4-methylphenethyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(4-methylphenyl) acetyl] thiophene- 3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(3-methoxyphenyl) acetyl] thiophene-3-sulfonamide; N- (4-bromo-3-methyl- 5-isoxazolyl) -3- (4-methylphenethyl) -5- (4-tolyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (4-methyl) Benzyl) -5- (4-tolyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (4 Methyl-trans-styryl) -5- (4-tolyl) thiophene-2-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) benzyl Thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(5-methyl-3-isoxazolyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4 -Bromo-3-methyl-5-isoxazolyl) -2-[(3-hydroxy-6-pyridazinyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-Bromo-3-methyl-5-isoxazolyl)- 3-{[3,4- (methylenedioxy) phenoxy] methyl} thiophene-2-sulfonamide; N- (4-bromo-3- Methyl-5-isoxazolyl) -2-[(4-methyl) (cinnamyl)] thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- [3,4- ( Methylenedioxy) phenethyl] thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- [3,4- (methylenedioxy) -trans-styryl] thiophene-2- Sulfonamide; N- (4-Bromo-3-methyl-5-isoxazolyl) -2-[(4-methyl) phenethyl] thiophene-3-sulfonamide; N- (3,4-dimethyl-5-isoxazolyl)- 2- (4-Tolylacetylphenyl) thiophene-3-sulfonamide; N- (3,4-dimethyl-5-isoxazolyl) -2- [3,4 (Methylenedioxy) phenylacetyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [2-hydroxy-4-methylphenyl) aminocarbonyl] thiophene-3- Sulfonamide; and other compounds such as those shown in Table 1 not specifically exemplified herein.

  For example, N- (4-bromo-3-methyl-5-isoxazolyl) -3- [2-methyl-4,5- (methylenedioxy) cinnamyl] thiophene-2-sulfonamide; N- (4-bromo- 3-methyl-5-isoxazolyl) -3- [2- (hydroxymethyl) -4,5- (methylenedioxy) cinnamyl] thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5- Isoxazolyl) -3- {2-[(tetrahydro-4H-pyran-2-yloxy) methyl] -4,5- (methylenedioxy) cinnamyl] thiophene-2-sulfonamide and N- (4-bromo-3- Methyl-5-isoxazolyl) -3- (2,4-dimethylcinnamyl) thiophene-2-sulfonamide was converted to N- (4-bromo-3-methyl-5-i Oxazolyl) -3 was prepared in the same manner as in the case of [3,4- (methylenedioxy) - - trans styryl] thiophene-2-sulfonamide. N- (4-Bromo-3-methyl-5-isoxazolyl) -3- [2-methyl-4,5- (methylenedioxy) phenethyl] thiophene-2-sulfonamide and N- (4-bromo-3- Methyl-5-isoxazolyl) -2- (2,4,6-trimethylphenethyl) thiophene-3-sulfonamide is converted to N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(4-methyl ) Phenethyl] thiophene-3-sulfonamide was prepared in a similar manner (see Example 24).

  N- (4-Bromo-3-methyl-5-isoxazolyl) -3-{[2-propyl-4,5- (methylenedioxy) phenoxy] methyl} thiophene-2-sulfonamide was converted to N- (4- Bromo-3-methyl-5-isoxazolyl) -3-[(4-methylphenoxy) methyl] thiophene-2-sulfonamide and N- (4-bromo-3-methyl-5-isoxazolyl) -3-{[3 , 4- (Methylenedioxy) phenoxy] methyl} thiophene-2-sulfonamide. N- (4-bromo-3-methyl-5-isoxazolyl) -2- [2-methyl-4,5- (methylenedioxy) phenethyl] thiophene-3-sulfonamide was converted to N- (4-bromo-3 -Methyl-5-isoxazolyl) -2-[(3,4-methylenedioxy) phenethyl] thiophene-3-sulfonamide. N- (4-Bromo-3-methyl-5-isoxazolyl) -3- (2-tolyl) thiophene-2-sulfonamide; N- (4-Bromo-3-methyl-5-isoxazolyl) -3- (3 -Tolyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (2-tolyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl) -5-isoxazolyl) -3- (3-methoxyphenyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (3-methoxyphenyl) thiophene-2-sulfone Amide; N- (4-Bromo-3-methyl-5-isoxazolyl) -3- (2-methoxyphenyl) thiophene-2-sulfonamide; N- (4-B Mo-3-methyl-5-isoxazolyl) -3- (4-ethylphenyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (4-propylphenyl) Thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (4-isopropylphenyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5) -Isoxazolyl) -3- (4-butylphenyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (2,4-dimethylphenyl) thiophene-2-sulfone Amide; N- (4-Bromo-3-methyl-5-isoxazolyl) -3- (4-isobutylphenyl) thiophene-2-sulf N- (4-bromo-3-methyl-5-isoxazolyl) -3- (4-isopentylphenyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl)- 3- (2-Methyl-4-propylphenyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (4-isobutyl-2-methylphenyl) thiophene-2 Compounds such as -sulfonamide and N- (4-bromo-3-methyl-5-isoxazolyl) -3- (4-isopentyl-2-methylphenyl) thiophene-2-sulfonamide can be prepared using N- (4-bromo- 3-methyl-5-isoxazolyl) -3-[(3,4-methylenedioxy) phenyl] thiophene-2-sulfonamide It was produced in the same manner as the method (see Example 125 of International Patent Application Publication WO 96/31492).

  N- (4-bromo-3-methyl-5-isoxazolyl) -2- [2-methyl-4,5- (methylenedioxy) phenethyl] thiophene-3-sulfonamide was converted to N- (4-bromo-3 -Methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) phenethyl] thiophene-3-sulfonamide (Example 22). N- (4-Bromo-3-methyl-5-isoxazolyl) -2- [2-methyl-4,5- (methylenedioxy) cinnamyl] thiophene-3-sulfonamide was converted to N- (4-bromo-3 -Methyl-5-isoxazolyl) -2-[(4-methyl) (cinnamyl)] thiophene-3-sulfonamide (Example 23).

  N- (4-Bromo-3-methyl-5-isoxazolyl) -2-{[3,4- (methylenedioxy) phenoxy] methyl} thiophene-3-sulfonamide; N- (4-Bromo-3-methyl -5-isoxazolyl) -2-[(2,4,6-trimethylphenoxy) methyl] thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2-{[4 5- (methylenedioxy) -2-propylphenoxy] methyl} thiophene-3-sulfonamide was converted to N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(4-methylphenoxy) methyl]. Prepared in a similar manner to thiophene-3-sulfonamide (Example 25).

  These compounds or the corresponding N- (4-halo-3-methyl-5-isoxazolyl), N- (4-halo-5-methyl-3-isoxazolyl), N- (3, 4-dimethyl-5-isoxazolyl), N- (4-halo-5-methyl-3-isoxazolyl), N- (4-halo-3-methyl-5-isoxazolyl), N- (4,5-dimethyl- 3-isoxazolyl) derivatives can also be prepared and used according to the methods described herein. Pharmaceutically acceptable derivatives such as salts, especially sodium salts, are formulated according to the methods described herein.

Example 37
Other compounds that can be prepared by the above method or conventional variations of the method include:
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-methylphenylaminocarbonyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-acetylphenylaminocarbonyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-methoxycarbonylphenylaminocarbonyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-carboxylphenylaminocarbonyl) thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-methanesulfonylphenylaminocarbonyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [2,3,4-trimethoxy-6- (cyanomethyl) phenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [2,3,4-trimethoxy-6- (2-hydroxyethyl) phenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-methylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-acetylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-methoxycarbonylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-carboxylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-methanesulfonylphenylaminocarbonyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-cyanophenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-cyanomethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6- (2-hydroxyethyl) phenylaminocarbonyl] thiophene-3-sulfone An amide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2,6-dimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-acetyl-2-methylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methoxycarbonyl-2-methylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-carboxyl-2-methylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methoxy-2-methylphenylaminocarbonyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methanesulfonyl-2-methylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-cyano-2-methylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6- (cyanomethyl) -2-methylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6- (2-hydroxyethyl) -2-methylphenylaminocarbonyl] thiophene-3-sulfone An amide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-cyano-6-methylphenylaminocarbonyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methoxy-2-cyanophenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-acetyl-6-methylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methoxy-2-acetylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-cyano-2,4,6-trimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-carboxyl-2,4,6-trimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-hydroxymethyl-2,4,6-trimethylphenylaminocarbonyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-methanesulfonyl-2,4,6-trimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-cyanomethyl-2,4,6-trimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3- (2-hydroxyethyl) -2,4,6-trimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3- (carboxymethyl) -2,4,6-trimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (4-cyano-2,6-dimethylphenylaminocarbonyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (4-carboxyl-2,6-dimethylphenylaminocarbonyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [4- (hydroxymethyl) -2,6-dimethylphenylaminocarbonyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [4- (2-hydroxyethyl) -2,6-dimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [4- (cyanomethyl) -2,6-dimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [4- (carboxylmethyl) -2,6-dimethylphenylaminocarbonyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (4-methanesulfonyl-2,6-dimethylphenylaminocarbonyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-methylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-acetylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-methoxycarbonylphenylacetyl) thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-carboxylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2,3,4-trimethoxy-6-methanesulfonylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [2,3,4-trimethoxy-6- (cyanomethyl) phenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [2,3,4-trimethoxy-6- (2-hydroxyethyl) phenylacetyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-methylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-acetylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-methoxycarbonylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6-carboxylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy-2-methoxy-6-methanesulfonyl) phenylacetyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6- (cyano) phenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6- (cyanomethylphenylacetyl] thiophene-3-sulfonamide;
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-methoxy-6- (2-hydroxyethyl) phenylacetyl] thiophene-3-sulfonamide ;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2,6-dimethylphenylacetyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-acetyl-2-methylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methoxycarbonyl-2-methylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-carboxyl-2-methylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methoxy-2-methylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methanesulfonyl-2-methylphenylacetyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-cyano-2-methylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6- (cyanomethyl) -2-methylphenylacetyl] thiophene-3-sulfonamide;
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6- (2-hydroxyethyl) -2-methylphenylacetyl] thiophene-3-sulfonamide ;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-cyano-6-methylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methoxy-2-cyanophenylacetyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -2-acetyl-6-methylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) -6-methoxy-2-acetylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-cyano-2,4,6-trimethylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-carboxyl-2,4,6-trimethylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-hydroxymethyl-2,4,6-trimethylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3-methanesulfonyl-2,4,6-trimethylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3- (cyanomethyl) -2,4,6-trimethylphenylacetyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3- (2-hydroxyethyl) -2,4,6-trimethylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3- (carboxylmethyl) -2,4,6-trimethylphenylacetyl] thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (4-cyano-2,6-dimethylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (4-carboxyl-2,6-dimethylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- (4-hydroxymethyl-2,6-dimethylphenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [4- (2-hydroxyethyl) -2,6- (dimethyl) phenylacetyl) thiophene-3-sulfonamide;
N- (4-chloro-3-methyl-5-isoxazolyl) -2- [4-cyanomethyl-2,6- (dimethyl) phenylacetyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [4- (carboxylmethyl) -2,6-dimethylphenylacetyl] thiophene-3-sulfonamide and N- (4-chloro-3- Examples include, but are not limited to, methyl-5-isoxazolyl) -2- (4-methanesulfonyl-2,6-dimethylphenylacetyl) thiophene-3-sulfonamide. Pharmaceutically acceptable derivatives such as salts, in particular sodium salts, are used in the formulations described herein.

Example 38
Interesting thienyl In the present invention -, furyl - and pyrrole - such sulfonamides, Ar ² contains a heterocyclic ring, the ET _A receptor or ET _B 10 [mu] M for the receptor or from much lower _{IC 50} concentrations activity Other compounds having can be prepared by methods similar to those described in the above examples, or were actually prepared (see, eg, Table 1). Such compounds include N- (4-bromo-3-methyl-5-isoxazolyl) -2-carboxyl-1-methylindole-3-sulfonamide; N- (4-chloro-3-methyl-5- Isoxazolyl) -2-[(4-oxacyclohexyl) oxycarbonyl] thiophene-3-sulfonamide; 2- [3,4- (methylenedioxy) phenylacetyl] thiophene-3-sulfonamide; N- (4-chloro -3-methyl-5-isoxazolyl)-{2- [3,4- (methylenedioxy) phenyl] acetyl} thiophene-3-sulfonamide oxime; N- (4-chloro-3-methyl-5-isoxazolyl) ) -2-Phenylbenzo [b] thiophenesulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) 2-[(4-Tolyl) aminocarbonyl] -1-methylindole-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(4-methoxyphenoxy) carbonyl] thiophene N- (4-Bromo-3-methyl-5-isoxazolyl) -1- [3,4- (methylenedioxy) benzyl] indole-2-sulfonamide; N- (4-Bromo- 3-methyl-5-isoxazolyl) -2-[(4-methylphenoxy) carbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(4-methoxy Phenyl) acetyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -6-methoxy- -[3,4- (methylenedioxy) benzyl] benzo [b] thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3-[(4-methylphenoxy) methyl Thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(4-methylphenoxy) methyl] thiophene-3-sulfonamide;

N- (4-Bromo-3-methyl-5-isoxazolyl) -3- (4-methyl-trans-styryl) thiophene-2-sulfonamide; N- (4-Bromo-3-methyl-5-isoxazolyl)- 3- (4-methylphenethyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2-[(4-methylphenyl) acetyl] thiophene-3-sulfonamide; N -(4-Chloro-3-methyl-5-isoxazolyl) -2-[(3-methoxyphenyl) acetyl] thiophene-3-sulfonamide; N- (4-Chloro-3-methyl-5-isoxazolyl) -2 -{1-hydroxy-1- [3,4- (methylenedioxy) benzyl] ethyl} thiophene-3-sulfonamide; N-4- (bromo- -Methyl-5-isoxazolyl) -3- (4-methylphenethyl) (4-tolyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (4-methyl Benzyl) -5- (4-tolyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (4-methyl-trans-styryl) -5- (4- Tolyl) thiophene-2-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [β, β- (ethylenedioxy) 3,4- (methylenedioxy) phenethyl] thiophene 3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [β- (dimethylamino) -3,4- (methylenedioxy) phenethyl Thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- {α-hydroxy- [3,4- (methylenedioxy) phenyl] acetyl} thiophene-3-sulfonamide; N- (4-chloro -5-methyl-3-isoxazolyl) -2- [3,4- (methylenedioxy) benzyl] benzo [b] thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3-styrylthiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2-styrylthiophene-3-sulfonamide; N- (4-bromo-3-methyl-5- Isoxazolyl) -2- (benzoylamino) thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2- [ Phenyl) methylaminocarbonyl] thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -5- (phenylthio) furan-2-sulfonamide; N- (4-bromo-3- Methyl-5-isoxazolyl) -5- (hydroxymethyl) furan-2-sulfonamide;

N- (4-Bromo-3-methyl-5-isoxazolyl) -5- (carbomethoxy) furan-2-sulfonamide; N- (4-Bromo-3-methyl-5-isoxazolyl) -2,5-dimethyl Furan-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2- (diisopropylaminocarbonyl) thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5- Isoxazolyl) -2- (diethylaminocarbonyl) thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -5-styrylfuran-2-sulfonamide; N- (4-bromo-3 -Methyl-5-isoxazolyl) -5-styrylthiophene-2-sulfonamide; N- (4-chloro-3-methyl- -Isoxazolyl) -2- [3,4- (methylenedioxy) benzyl] -5- (dimethylamino) benzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) ) -2- [3,4- (methylenedioxy) benzyl] -7-methoxybenzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [ 3,4- (methylenedioxy) benzyl] -7-phenoxybenzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- ( Methylenedioxy) benzyl] -5-methoxybenzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [ , 4- (methylenedioxy) benzyl] -5-isobutylaminobenzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- ( Methylenedioxy) benzyl] -5-benzylaminobenzo [b] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) phenoxy] benzo [b] thiophene-3-sulfonamide; N- (4-chloro-3- Methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) phenoxy] -5-dimethylaminobenzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5- Isoxazolyl) -2-[(3,4-methylenedioxy) phenyl] acetyl-5-dimethylaminobenzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl)- 2- [3,4- (methylenedioxy) benzylcarbonyl] -N-methylindole-3-sulfonamide; N- (4-chloro-3-methyl-5-i Oxazolyl) -2- [3,4- (methylenedioxy) phenoxycarbonyl] indole-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylene Dioxy) phenoxycarbonyl] -N-methylindole-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) phenoxycarbonyl] indole- 3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) benzyl] -N-methylindole-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) benzyl] indole-3-sulfonamide; N- (4-chloro-3-methyl-5- Isoxazolyl) -2- [3,4- (methylenedioxy) benzyloxycarbonyl] -7- (N, N-dimethylamino) benzo [b] thiophene-3-sulfonamide; N- (4-chloro-3- Methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) benzyl] -7- (N, N-dimethylamino) benzo [b] thiophene-3-sulfonamide; N- (4-chloro- 3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) benzoyl] -7- (N, N-dimethyl) amino) benzo [b] thiophene-3-sulfone De; N-(4-chloro-3-methyl-5-isoxazolyl) -7- (N, N- dimethylamino) benzo [b] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -7- (methoxycarbonyl) benzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2 -[3,4- (methylenedioxy) benzyl] -7- (methoxy) benzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -7- (methoxy ) Benzo [b] thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -2- (4-methylphenethyl) thiophene-3-sulfonamide; N- (4-bromo-) 3-methyl-5-isoxazolyl) -2- (trans-4-methylcinnamyl) thiophene-3-sulfonamide; N- (4-bromo-3-methyl- -Isoxazolyl) -3- (4-methylphenethyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (3-methylphenethyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- (2-methylphenethyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3- ( Trans-4-methylcinnamyl) thiophene-2-sulfonamide;

N- (4-Bromo-3-methyl-5-isoxazolyl) -3- (trans-3-methylcinnamyl) thiophene-2-sulfonamide; N- (4-Bromo-3-methyl-5-isoxazolyl)- 3- (trans-2-methylcinnamyl) thiophene-2-sulfonamide; N- (4-bromo-3-methyl-5-isoxazolyl) -3-[(4-methylphenoxy) methyl] thiophene-2-sulfone N- (4-Bromo-3-methyl-5-isoxazolyl) -3- [3,4- (methylenedioxy) phenethyl] thiophene-2-sulfonamide; N- (4-Chloro-3-methyl-) 5-isoxazolyl) -2-{(3,4- (dimethoxy) phenyl] acetyl)} thiophene-3-sulfonamide; N- (4-chloro-3-methyl) Ru-5-isoxazolyl) -2-[(3,5-dimethoxyphenyl) acetyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(3,4 , 5-trimethoxyphenyl) acetyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) benzylsulfonyl] thiophene-3 -Sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- [3,4- (methylenedioxy) benzylsulfinyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5 -Isoxazolyl) -2- [3,4- (methylenedioxy) benzylsulfenyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- {1- (dimethyl Amino) -2- [3,4- (methylenedioxy) phenyl} ethylthiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- {1-methylamino)- 2- [3,4- (methylenedioxy) phenyl] ethyl} thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) 2- {1- (methoxylimino) -2- [3,4- (methylenedioxy) phenyl] ethyl} thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2 -{1- (carboxyl) -2- [3,4- (methylenedioxy) phenyl] ethyl} thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- { 2- (carboxyl) -1- [3,4- (methylenedioxy) benzyl] vinyl} thiophene-3-sulfonamide;

N- (4-Chloro-3-methyl-5-isoxazolyl) -2- {3- [3,4- (methylenedioxy) phenyl] -1,2,4-oxadiazol-5-yl} thiophene- 3-sulfonamide and N- (4-chloro-3-methyl-5-isoxazolyl) -2- {3- [3,4- (methylenedioxy) benzyl] -1,2,4-oxadiazole-5 -Yl} thiophene-3-sulfonamide and the like, but are not limited thereto.

  Another compound includes N- (4-chloro-3-methyl-5-isoxazolyl) -2-{[2- (methanesulfonyl) -4,5- (methylenedioxy) phenyl] aminocarbonyl} thiophene-3. -Sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-{[3,4- (methylenedioxy) -6-carboxylphenyl] aminocarbonyl} thiophene-3-sulfonamide; N -(4-Chloro-3-methyl-5-isoxazolyl) -2-{[4,5- (methylenedioxy) -2- (methoxycarbonyl] phenyl} aminocarbonyl} thiophene-3-sulfonamide; N- ( 4-chloro-3-methyl-5-isoxazolyl) -2-{[2-cyano-4,5- (methylenedioxy) phenyl] aminocarbonyl Thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-{[4,5- (methylenedioxy) -2-hydroxymethyl) phenyl] aminocarbonylthiophene-3- Sulfonamide; N- (4-Chloro-3-methyl-5-isoxazolyl) -2-[(2-acetyl-4-methylphenyl] aminocarbonyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2-{[2- (methanesulfonyl) -4-methylphenyl] aminocarbonyl} thiophene-3-sulfonamide; N- (4-chloro-3 -Methyl-5-isoxazolyl) -2-[(2-carboxyl-4-methylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [ (2-methoxycarbonyl-4-methylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(2-cyano-4-methylphenyl) Aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [2- (hydroxymethyl) -4-methylphenyl] aminocarbonyl} thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(3,4-dimethoxy-6 -Acetylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-{[2- (methanesulfonyl) -4,5-dimethoxyphenyl] aminocarbonyl } Thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(4,5-dimethoxy-2-carboxylphenyl) aminocarbonyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(4,5-dimethoxy-2-methoxycarboxyl) phenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro- 3-methyl-5-isoxazolyl) -2- [2-cyano (4,5-dimethoxyphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2 -(4,5-dimethoxy-2-hydroxymethyl) phenylaminocarbonylthiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-{[2-acetyl-4,5 -(Methylenedioxy) phenyl] acetyl} thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5- Soxazolyl) -2-{[2- (methanesulfonyl) -4,5- (methylenedioxy) phenyl] acetyl} thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl)- 2-{[carboxyl-4,5- (methylenedioxy) -2-phenylacetylthiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-{[4,5 -(Methylenedioxy) -2-methoxycarbonylphenyl] acetylthiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- {2-cyano [4,5- (methylene Dioxy) -phenyl] acetyl} thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2- {2-hydroxymethyl [4,5- (methylenedioxy) -phenyl] acetyl} thiophene-3-sulfonamide; N- (4- Chloro-3-methyl-5-isoxazolyl) -2-[(2,4-dimethoxy) phenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2 -[(4-Methoxy-2-methylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(2,3-dimethylphenyl) amino Carbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(2,4-dimethyl) Phenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(2,5-dimethylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N -(4-Chloro-3-methyl-5-isoxazolyl) -2-[(2,6-dimethylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-Chloro-3-methyl-5-isoxazolyl) ) -2-[(3,4-Dimethylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-Chloro-3-methyl-5-isoxazolyl) -2-[(2,5-dimethylphenyl) Aminocarbonyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(3,5-dimethyl) phenylaminocarbonylthiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) ) -2-[(2-methoxy-6-methylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(2,4,6 -Trimethylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(4-methoxy-2-methylphenyl) aminocarbonyl] thiophene-3- Sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [2-ethyl (4-methoxy-) pheny ) Aminocarbonyl) thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(2-isopropyl-4-methoxy-phenyl) aminocarbonyl] thiophene-3-sulfonamide N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(2-propyl-4-methoxy-phenyl) aminocarbonyl] thiophene-3-sulfonamide;

N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(4-methoxy-2-biphenylaminocarbonyl] -thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5 -Isoxazolyl) -2-{[3,4- (methylenedioxy) -6-methylphenyl) acetyl] -thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2 -{[3,4- (methylenedioxy) -6-ethylphenyl) acetyl} thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-{[3,4 -(Methylenedioxy) -6-methoxyphenyl] acetyl} thiophene-3-sulfonamide and the like, but are not limited thereto. Pharmaceutically acceptable derivatives such as salts, in particular sodium salts, are used in the formulations described herein.

Example 39
N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide
A. A solution of 2′-amino-3 ′, 5′-dimethylacetophenone BCl ₃ in methylene chloride (1.0 M, 25 mL) was brought to 0 ° C., and 2,4-dimethylaniline (3.03 g, 25 mmol) in 1,2- Dichloroethane (25 mL) solution was added slowly. Next, acetonitrile (25 mL) was added dropwise at 0 ° C. Under a gentle and steady flow of nitrogen, the mixture was heated at a bath temperature of 100 ° C. for 2 days to remove low boiling methylene chloride. The reaction was cooled to 0 ° C., quenched with 2N HCl (about 25 mL), and the mixture was heated at 80 ° C. until a homogeneous solution was obtained (about 20 minutes). This was allowed to cool to room temperature and separated into two layers. The aqueous layer was neutralized with sodium bicarbonate until no more gas was observed and a large amount of precipitate was formed. The mixture was extracted with chloroform (about 30 mL) and the organic layers were combined and concentrated. The residue was dissolved in ethyl acetate (50 mL) and washed with 1N NaOH (40 mL). The organic layer was dried (MgSO ₄ ), the solid was filtered off and the filtrate was concentrated. The oily residue was dissolved in ethyl acetate (about 5 mL) and allowed to stand at room temperature for 24 hours. The resulting yellow precipitate was filtered to give 2′-amino-3 ′, 5′-dimethylacetophenone (1.3 g, 30%).

B. N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide 2'-amino-3 ', 5 '-Dimethylacetophenone (1.9 g, 11.66 mmol) in methylene chloride (20 mL) at room temperature with N- (4-chloro-3-methyl-5-isoxazolyl) -N-methoxymethyl-3-sulfamoyl-2 -Thiophenecarbonyl chloride (Example 51) (1 g, 2.86 mmol) was added. The mixture was stirred for 10 hours during which a large amount of yellow precipitate formed. The reaction was concentrated and the residue was diluted with ethyl acetate (50 mL) and washed with 1N HCl (50 mL). The organic layer was concentrated and the residue was dissolved in methanol (30 mL) and then concentrated HCl (15 mL) was added. The mixture was heated at reflux for 2 hours, then cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with water (2 × 200 mL). The organic layer was separated, dried (MgSO ₄ ), the solid was filtered off, and the filtrate was concentrated. The residue was purified by reverse phase HPLC to give N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2- Thiophenecarboxamide was obtained (580 mg, 43%).

Example 40
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-propionylphenyl) -2-thiophenecarboxamide
A. 2′-amino-3 ′, 5′-dimethylpropiophenone As in the case of 2′-amino-3 ′, 5′-dimethylacetophenone (Example 39) except that propionitrile was used instead of acetonitrile. 2′-amino-3 ′, 5′-dimethylpropiophenone was synthesized.

B. 3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-propionylphenyl) -2-thiophenecarboxamide 2-amino-3 ′, 5 ′ -N- (2-acetyl-4,6-dimethylphenyl) -3-((((4-chloro-)) except that 2'-amino-3 ', 5'-dimethylpropiophenone was used instead of dimethylacetophenone 3-Methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide (Example 39) as in 3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2,4-dimethyl-6-propionylphenyl) -2-thiophenecarboxamide was synthesized.

Example 41
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-isobutyl-4,6-dimethylphenyl) -2-thiophenecarboxamide
A. 2′-amino-3 ′, 5′-dimethyl-2-methylpropiophenone 2′-amino-3 ′, 5′-dimethylacetophenone (Example 39) except that isobutyronitrile was used instead of acetonitrile In the same manner as described above, 2′-amino-3 ′, 5′-dimethyl-2-methylpropiophenone was synthesized.

B. 3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-isobutyryl-4,6-dimethylphenyl) -2-thiophenecarboxamide 2′-amino-3 ′, 5 N- (2-acetyl-4,6-dimethylphenyl) -3-((, except that 2'-amino-3 ', 5'-dimethyl-2-methylpropiophenone was used instead of' -dimethylacetophenone. In the same manner as for (4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide (Example 39), 3-((((4-chloro-3-methyl-5-isoxazolyl) ) Amino) sulfonyl) -N- (2-isobutyryl-4,6-dimethylphenyl) -2-thiophenecarboxamide was synthesized.

Example 42
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclohexylcarbonyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide
A. Cyclohexyl 2-amino-3,5-dimethylphenyl ketone In the same manner as in 2'-amino-3 ', 5'-dimethylacetophenone (Example 39) except that cyclohexyl cyanide was used instead of acetonitrile. 2-Amino-3,5-dimethylphenyl ketone was synthesized.

B. 3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclohexylcarbonyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide 2'-amino-3 N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chlorophenyl) was used except that cyclohexyl 2-amino-3,5-dimethylphenylketone was used instead of ', 5'-dimethylacetophenone. 3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl as in the case of -3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide (Example 39) ) -N- (2- (cyclohexylcarbonyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide .

Example 43
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclopropylcarbonyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide
A. Cyclopropyl 2-amino-3,5-dimethylphenylketone As in the case of 2′-amino-3 ′, 5′-dimethylacetophenone (Example 39) except that cyclopropyl cyanide was used instead of acetonitrile. Cyclopropyl 2-amino-3,5-dimethylphenyl ketone was synthesized.

B. 3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2- (cyclopropylcarbonyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide 2′-amino- N- (2-acetyl-4,6-dimethylphenyl) -3-((((4)) except that cyclopropyl 2-amino-3,5-dimethylphenyl ketone was used instead of 3 ′, 5′-dimethylacetophenone. -Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide (Example 39) in the same manner as 3-(((4-chloro-3-methyl-5-isoxazolyl) amino ) Sulfonyl) -N- (2- (cyclopropylcarbonyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide .

Example 44
N- (2-benzoyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide
A. In the same manner as in the case of 2′-amino-3 ′, 5′-dimethylacetophenone (Example 39) except that benzonitrile was used instead of 2-amino-3,5-dimethylphenylphenylketone acetonitrile, Amino-3,5-dimethylphenyl phenyl ketone was synthesized.

B. N- (2-benzoyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide 2'-amino-3 ', 5 N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3- Methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide (Example 39) is analogous to N- (2-benzoyl-4,6-dimethylphenyl) -3-(((4-chloro -3-Methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide was synthesized.

Example 45
N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-methyl-2-thiophenecarboxamide
A. N- (4-Chloro-3-methyl-5-isoxazolyl) -3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid N- (4-chloro-3-methyl-5-isoxazolyl) -3-sulfamoyl-2 A solution of thiophenecarboxylic acid (6 g, 18.60 mmol) in dehydrated tetrahydrofuran (240 mL) was brought to −78 ° C. under nitrogen, and nBuLi (2.5 M hexane solution, 30 mL, 74.4 mmol) was added thereto. The mixture was stirred at this temperature for 2 hours before methyl iodide (6.6 g, 74.4 mmol) was added. The mixture was poured into crushed ice and allowed to warm to room temperature. After acidification with conc. HCl to pH ˜1, the mixture was extracted with ethyl acetate (2 × 200 mL). The organic layers were combined, dried (MgSO ₄ ), the solid was filtered, the filtrate was concentrated, and N- (4-chloro-3-methyl-5-isoxazolyl) -3-sulfamoyl-5-methyl-2-thiophene. Carboxylic acid and starting material were obtained in a ratio of about 2: 1 (total weight 8.5 g).

B. N- (4-Chloro-3-methyl-5-isoxazolyl) -3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid To a solution of the product mixture of Example 45A (8.5 g) in THF (150 mL) was added diisopropyl. Ethylamine (9.62 g, 74.4 mmol) and bromomethyl methyl ether (90%, 7.75 g, 55.80 mmol) were added in that order. The mixture was stirred for 10 hours before morpholine (4.6 g, 55.80 mmol) was added to remove excess bromomethyl methyl ether. The reaction was stirred for an additional 30 minutes before it was diluted with ethyl acetate (150 mL) and washed with 1N HCl (200 mL). The organic layer was dried (MgSO ₄ ), the solid was filtered off and the filtrate was concentrated. The residue is chromatographed (10% ethyl acetate / hexane) to give methoxymethyl N- (4-chloro-3-methyl-5-isoxazolyl) -3-sulfamoyl-5-methyl-2-thiophenecarboxylate. It was. The carboxylic acid ester was hydrolyzed with 1N NaOH to give the corresponding carboxylic acid (3.5 g).

C. N- (4-chloro-3-methyl-5-isoxazolyl) -N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid chloride N- (4-chloro-3-methyl-5-isoxazolyl) Instead of -N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxylic acid, N- (4-chloro-3-methyl-5-isoxazolyl) -N-methoxymethyl-3-sulfamoyl-5-methyl-2- Except for using thiophenecarboxylic acid, as in the case of N- (4-chloro-3-methyl-5-isoxazolyl) -N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonyl chloride (Example 51), N- (4-Chloro-3-methyl-5-isoxazolyl) -N-methoxymethyl-3-sulfamoyl It was synthesized 5-methyl-2-thiophenecarboxylic acid chloride.

D. N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -5-methyl-2-thiophenecarboxamide N- (4- Chloro-3-methyl-5-isoxazolyl) -N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxylic acid chloride instead of N- (4-chloro-3-methyl-5-isoxazolyl) -N-methoxymethyl- N- (2-acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) except that 3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid chloride was used ) Amino) sulfonyl) -2-thiophenecarboxamide (Example 39) in the same manner as in N- (2-acetyl-4) 6-dimethylphenyl) -3 - (((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) was synthesized 5-methyl-2-thiophenecarboxamide.

Example 46
3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-hydroxyethaneimidoyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide N- (2- 2N of acetyl-4,6-dimethylphenyl) -3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thiophenecarboxamide (Example 39) (50 mg, 0.11 mmol) To a solution of NaOH (40 mL) and methanol (4 mL) was added hydroxylamine hydrochloride (4 g, 57.6 mmol). The mixture was stirred at 60 ° C. for 3 hours, then cooled to 0 ° C. and acidified with concentrated HCl to pH 1-2. The resulting white precipitate was filtered, washed with dilute acid, dehydrated by lyophilization and 3-(((4-chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -N- (2-hydroxy Ethaneimidoyl) -4,6-dimethylphenyl) -2-thiophenecarboxamide (45 mg, 87%) was obtained.

Example 47
3-(((3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thienyl) carbonyl) amino) -2,4,6-trimethylphenyl) methyl carbonate N ^2- (4-Chloro-3-methyl-5-isoxazolyl) -N- (3-hydroxy-2,4,6-trimethylphenyl) -3-sulfamoyl-2-thiophenecarboxamide (Example 52) (238 mg, 0.524 mmol ) Was brought to 0 ° C., and potassium tert-butoxide (177 mg, 1.57 mmol) was added thereto. After the mixture was stirred at this temperature for 30 minutes, methyl chloroformate (99.2 mg, 1.05 mmol) was added. The reaction mixture was poured into dilute acid containing ice, and the resulting precipitate was collected and purified by HPLC to give 3-((((((4-chloro-3-methyl-5-isoxazolyl)). Amino) sulfonyl) -2-thienyl) carbonyl) amino) -2,4,6-trimethylphenyl) methyl carbonate (186 mg, 70%) was obtained.

Example 48
3-(((3-(((4-Chloro-3-methyl-5-isoxazolyl) amino) sulfonyl) -2-thienyl) carbonyl) amino) -2,4,6-trimethylphenylcarbamate N ^2- (4 Of -chloro-3-methyl-5-isoxazolyl) -N- (3-hydroxy-2,4,6-trimethylphenyl) -3-sulfamoyl-2-thiophenecarboxamide (Example 52) (500 mg, 1.05 mmol) The dehydrated DMF solution was brought to 0 ° C., and potassium tert-butoxide (295 mg, 2.61 mmol) was added thereto. After the mixture was stirred at this temperature for 10 minutes, p-nitrophenyl chloroformate (317 mg, 1.57 mmol) was added. After stirring for about 1 minute, the reaction was treated with ammonium hydroxide (8 mL) and stirring was continued at room temperature for 2 hours. The reaction mixture was poured into dilute acid containing ice, and the resulting precipitate was collected and purified by HPLC to give 3-((((((4-chloro-3-methyl-5-isoxazolyl)). Amino) sulfonyl) -2-thienyl) carbonyl) amino) -2,4,6-trimethylphenylcarbamate (213 mg, 42%) was obtained.

Example 49
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- (2- (3-methoxy-2,4,6-trimethylphenyl) acetyl) -3-thiophenecarboxamide
A. N- (4-Chloro-3-methyl-5-isoxazolyl) -3-sulfamoyl-2-thiophenecarbonitrile N- (4-Chloro-3-methyl-5-isoxazolyl) -3-sulfamoyl-2-thiophenecarboxamide ( A solution of 5 g, 15.6 mmol) of POCl ₃ (50 mL) was heated at 60 ° C. for 3 hours. The reaction was cooled to room temperature, poured into crushed ice (about 250 g), the mixture with ice was shaken and stirred until all the ice was melted (about 2 hours). The mixture was extracted with ethyl acetate, the organic layer was dried (MgSO ₄ ), the solid was filtered off, the filtrate was concentrated and dried under reduced pressure to give N- (4-chloro-3-methyl-5-isoxazolyl)- 3-sulfamoyl-2-thiophenecarbonitrile was obtained (4.8 g, about 100%).

B. 5-chloromethyl-, except that 1-methoxy-2,4,6-trimethylbenzene was used instead of 3-methoxy-2,4,6-trimethylbenzyl chloride 5-methylbenzo [d] [1,3] dioxole 3-Methoxy-2,4,6-trimethylbenzyl chloride was synthesized in the same manner as in the case of 6-methylbenzo [d] [1,3] dioxole (Example 7).

C. N-(4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-methoxy-2,4,6-trimethylphenyl) acetyl) -3-thiophenesulfonamide N ² - methoxy -N ² N- (4-Chloro-3-methyl-5-isoxazolyl) -3-sulfamoyl instead of -methyl-3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl) -2-thiophenecarboxamide 4-Chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) except that 2-thiophenecarbonitrile (Example 49A) was used. As in the case of (acetyl) -3-thienylsulfonamido) isoxazole (Example 7), N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-Methoxy-2,4,6-trimethylphenyl) acetyl) -3-thiophenesulfonamide was synthesized.

Example 50
N- (4-Chloro-3-methyl-5-isoxazolyl) -2- (2- (3-hydroxy-2,4,6-trimethylphenyl) acetyl) -3-thiophenesulfonamide N- (4-chloro- Chlorination of 3-methyl-5-isoxazolyl) -2- (2- (3-methoxy-2,4,6-trimethylphenyl) acetyl) -3-thiophenesulfonamide (Example 49) (50 mg, 0.107 mmol) The methylene (20 mL) solution was brought to 0 ° C., and BBr ₃ (1M methylene chloride solution, 3 mL, 3.0 mmol) was added to it. The resulting mixture was stirred at 0 ° C. for 1 hour and at room temperature for 8 hours and then poured into crushed ice (about 100 g). The aqueous mixture was stirred until all the ice melted and extracted with methylene chloride (2 x 100 mL). The organic layers were combined and concentrated, and the residue was purified by HPLC to give N- (4-chloro-3-methyl-5-isoxazolyl) -2- (2- (3-hydroxy-2,4,6-trimethyl). Phenyl) acetyl) -3-thiophenesulfonamide (47 mg, 85%) was obtained.

Example 51
N- (4-Chloro-3-methyl-5-isoxazolyl) -N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonyl chloride
A. 5-Amino-4-chloro-3-methylisoxazole To a solution of 5-amino-3-methylisoxazole (9.8 g, 100 mmol) in methylene chloride (200 mL) was added N-chlorosuccinimide (14.7 g, 110 mmol). Was added at 0 ° C. over 20 minutes. The reaction mixture was stirred at room temperature for 2 hours. As workup, the reaction mixture was concentrated and partitioned between 1N NaOH (150 mL) and ethyl acetate (400 mL). The organic layer was washed with 1N NaOH, water, brine, dried over MgSO ₄ and concentrated to give a brown solid. For purification, the product was reprecipitated from chloroform / hexane and then recrystallized from ethyl acetate / hexane to give 5-amino-4-chloro-3-methylisoxazole as a brownish solid (5 .5g, 41%).

B. 2-Carbomethoxy-3- [N- (4-chloro-3-methylisoxazol-5-yl)] thiophenesulfonamide NaH in 60% mineral oil suspension (8.5 g, 0.21 mol) in THF (100 mL ) Was brought to −20 ° C., and a solution of 5-amino-4-chloro-3-methylisoxazole (12.4 g, 92.4 mmol) in dehydrated THF (65 mL) was added over 20 minutes under nitrogen. After stirring for 10 minutes, a solution of 2-carbomethoxy-3-thiophenesulfonyl chloride (22.2 g, 92.4 mmol) in THF (65 mL) was added at −20 ° C. over 15 minutes. The reaction mixture was stirred for 10 minutes and then quenched with H ₂ O (5 mL) at that temperature. For workup, the reaction mixture was poured into 4N HCl and the product was extracted with ethyl acetate. The combined organic layers were washed with water and the compound was extracted with half-saturated NaHCO ₃ . The combined base solution was decolorized with activated carbon, cooled to 0 ° C. and acidified with 4N HCl. The product was isolated by filtration, washed with water and dried to give 2-carbomethoxy-3- [N- (4-chloro-3-methylisoxazol-5-yl)] thiophenesulfonamide as a white powder. Obtained (23.4 g, 75%).

C. 2-Carbomethoxy-3- [N- (4-chloro-3-methylisoxazol-5-yl) -N-methoxymethyl] thiophenesulfonamide 2-carbomethoxy-3- [N- (4-chloro-3 -Methylisoxazol-5-yl)] thiophenesulfonamide (3.3 g, 10.0 mmol) in THF (50 mL) at 0 ° C. was added diisopropylethylamine (1.9 g, 15.0 mmol) followed by bromo Methyl methyl ether (1.5 g, 12.0 mmol) was added. The reaction mixture was stirred at room temperature overnight. As workup, the reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried over MgSO ₄ , concentrated, and 2-carbomethoxy-3- [N- (4-chloro-3-methylisoxazol-5-yl) -N-methoxymethyl. Thiophensulfonamide was obtained as a greenish oil (3.5 g, 90%).

D. 2-carboxy-3- [N- (4-chloro-3-methylisoxazol-5-yl) -N-methoxymethyl] thiophenesulfonamide 2-carbomethoxy-3- [N- (4-chloro-3- A mixed solution of methylisoxazol-5-yl) -N-methoxymethyl] thiophenesulfonamide (3.0 g, 7.8 mmol) in THF (30 mL) and 1N NaOH (30 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (5 mL). The aqueous solution was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO ₄ , concentrated, and 2-carboxy-3- [N- (4-chloro-3-methylisoxazol-5-yl) -N-methoxymethyl]. Thiophenesulfonamide was obtained as an oil (quantitative yield).

E. N- (4-Chloro-3-methyl-5-isoxazolyl) -N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonyl chloride 2-carboxy-3- [N- (4-chloro-3-methylisoxazole- To a mixed solution of 5-yl) -N-methoxymethyl] thiophenesulfonamide (1.5 g, 4.1 mmol) in THF (10 mL) and chloroform (5 mL) at 0 ° C. is added pyridine (1 drop), then A 2M oxalyl chloride solution (4.5 mL, 9.0 mmol) was added. The reaction mixture was stirred at room temperature overnight. As a workup, the reaction mixture was concentrated under reduced pressure to remove all volatiles. The desired product was obtained as a viscous oil that solidified on standing.

Example 52
N ² -(4-Chloro-3-methyl-5-isoxazolyl) -N- (3-hydroxy-2,4,6-trimethylphenyl) -3-sulfamoyl-2-thiophenecarboxamide
A. 3-acetoxy-2,4,6-trimethylaniline

To a solution of 2,4,6-trimethylphenol (10 g, 73.5 mmol) and triethylamine (11.1 g, 110.3 mmol) in ethyl acetate (200 mL) was added acetyl chloride (7.5 g, 95.6 mmol) at 0 ° C. It was dripped. The mixture was stirred overnight. The reaction was quenched with water and the organic layer was washed with 1N HCl. The organic layer was dehydrated and concentrated by a conventional method. The residue was nitrated with 70% HNO ₃ and concentrated H ₂ SO ₄ at room temperature. The brown reaction mixture was stirred for 1 hour and poured into ice water. The product was extracted with ethyl acetate and the extract was washed with water, dried over MgSO ₄ and concentrated to give the desired nitro compound. This compound was reduced in methanol by adding ammonium chloride and zinc in that order. The exothermic reaction was stirred vigorously until it returned to room temperature (2 hours). For workup, the crude mixture was filtered and the cake was washed with methanol. The methanol solution was concentrated and the residue was partitioned between ethyl acetate and 1N NaOH. The organic layer was dried over MgSO ₄ and concentrated to give 3-acetoxy-2,4,6-trimethylaniline.

B. N ² - and (4-chloro-3-methyl-5-isoxazolyl)-N-(3- hydroxy-2,4,6-trimethylphenyl) -3-sulfamoyl-2-thiophenecarboxamide The amine (Example 52A) The product of Example 51 is reacted in THF at 0 ° C. to give N ^2- (4-chloro-3-methyl-5-isoxazolyl) -N- (3-hydroxy-2,4,6-trimethylphenyl). ) -3-sulfamoyl-2-thiophenecarboxamide was synthesized. The reaction mixture was warmed to room temperature and stirred for 2 hours. For workup, the reaction mixture was poured into 0.05N HCl and the product was extracted with ethyl acetate. The organic layer was washed with 0.05N HCl, water, half-saturated NaHCO ₃ , water, brine, dried over MgSO ₄ and concentrated. Column chromatography (silica, 40% ethyl acetate / hexanes) Purification ^by, N 2 - (4-chloro-3-methyl-5-isoxazolyl)-N-(3- hydroxy-2,4,6-trimethylphenyl) -N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxamide was obtained. The carboxamide in THF-concentrated HCl was stirred at 65-72 ° C. for 3.5 hours. As a post treatment, the reaction mixture was cooled and poured into water. The product was taken up in ethyl acetate. The extract was washed with water, brine, saturated NaHCO ₃ , brine, dried over MgSO ₄ and concentrated to an oil. Upon deprotection of the MOM group, the acetoxy group was hydrolyzed to the corresponding hydroxyl group. N ^2- (4-chloro-3-methyl-5-isoxazolyl) -N- (3-hydroxy-2,4,6-trimethylphenyl) -3-sulfamoyl-2-thiophenecarboxamide was obtained as a solid (melting point 75 ˜78 ° C., 54%).

Example 53
Assay to identify compounds exhibiting endothelin antagonist activity and / or agonist activity

The possible compounds of endothelin antagonists, be confirmed by examining the ability to compete with ^{125 I-labeled} ET-1 for binding to human ET _A receptors or ET _B receptors present on isolated cell membranes. The effectiveness of test compounds as antagonists or agonists of endothelin's biological tissue response can also be assessed by measuring the effect on endothelin-induced contraction of isolated rat thoracic aortic rings. The ability of a compound to act as an antagonist or agonist of ET _B receptors can be compounds is evaluated by examining the ability to inhibit endothelin-1 induced prostacyclin release from cultured bovine aortic endothelial cells.

A. Endothelin binding inhibition - Binding Test 1: ET _A Inhibition of binding to the receptor TE671 cells (ATCC Accession No. HTB139) express ET _A receptors. The cells were grown to confluence in a T-175 flask. Cells from multiple flasks were collected by scraping, collected, and centrifuged at 190 × g for 10 minutes. The cells were resuspended in phosphate buffered saline (PBS) containing 10 mM EDTA using a homogenizer (Tenbroeck). The suspension was centrifuged at 57800 × g for 15 minutes at 4 ° C., and the pellet was resuspended in 5 mL of buffer A (5 mM HEPES buffer (pH 7.4) containing aprotinin (100 KIU / mL)) and frozen. And thawed once. 5 mL of buffer B (5 mM HEPES buffer (pH 7.4) containing 10 mM MnCl ₂ and 0.001% deoxyribonuclease type 1) was added, the suspension was inverted and incubated at 37 ° C. for 30 minutes. The mixture is centrifuged at 57800 × g according to the method described above, the pellet is washed twice with buffer A and resuspended in buffer C (30 mM HEPES buffer (pH 7.4) containing aprotinin (100 KIU / mL)). The final protein concentration was 2 mg / mL and stored at −70 ° C. until use.

The membrane suspension was diluted with binding buffer (150 mM NaCl, 5 mM MgCl ₂ , 30 mM HEPES buffer (pH 7.4) containing 0.5% bacitracin) to a concentration of 8 μg / 50 μL. ¹²⁵ I-endothelin-1 (3000 cpm, 50 mL) was added to (A) endothelin-1 (for non-specific binding) (final concentration 80 nM); (B) binding buffer (for total binding); or (C ) Added to any 50 μL of test compound (final concentration 1 nM-100 μM). A membrane suspension (50 μL) containing up to 8 μg of membrane protein was added to each of (A), (B) or (C). The mixture was shaken, incubated at 4 ° C. for 16-18 hours, and centrifuged at 2500 × g for 25 minutes at 4 ° C. Alternatively, incubation was performed at 24 ° C. Incubating at 24 ° C results in an IC ₅₀ concentration that is 2-10 times higher than when incubation is performed at 4 ° C. This should be noted when comparing IC ₅₀ concentrations between compounds provided in the present invention.

各試験は三連で行った。 The supernatant containing unbound radioactivity was removed by a gradient method, and the pellet was counted with a γ-counter (Genesys multiwell gamma counter). The degree of binding inhibition (D) was calculated according to the following formula:
[Formula 1]

Each test was done in triplicate.

B. Endothelin binding inhibition - Binding Test 2: Inhibition COS7 cells binding to ET _B receptors were transfected with DNA encoding ET _B receptors. The acquisition cells expressing human ET _B receptor, were grown in T-0.99 flasks until confluence. A membrane was obtained according to the method described above. The binding assay was performed according to the method described above using a membrane preparation diluted with binding buffer to a concentration of 1 μg / 50 μL.

That has been transfected with DNA encoding the ET _B receptor, were grown said COS7 cells expressing ET _B receptors at the surface in a T-175 flasks until confluence. Cells from multiple flasks were collected by scraping, collected, and centrifuged at 190 × g for 10 minutes. The cells were resuspended in phosphate buffered saline (PBS) containing 10 mM EDTA using a homogenizer (Tenbroeck). The suspension was centrifuged at 57800 × g for 15 minutes at 4 ° C., and the pellet was resuspended in 5 mL of buffer A (5 mM HEPES buffer (pH 7.4) containing aprotinin (100 KIU / mL)) and frozen. And thawed once. 5 mL of buffer B (5 mM HEPES buffer (pH 7.4) containing 10 mM MnCl ₂ and 0.001% deoxyribonuclease type 1) was added, the suspension was inverted and incubated at 37 ° C. for 30 minutes. The mixture was centrifuged at 57800 × g according to the method described above, the pellet was washed twice with buffer A and resuspended in buffer C (30 mM HEPES buffer (pH 7.4) containing aprotinin (100 KIU / mL)). The final protein concentration was 2 mg / mL.

  Binding assays were performed according to the method described above using membrane preparation diluted to give 1 μg / 50 μL of binding buffer.

C. Testing the activity of isolated rat thoracic aortic rings against endothelin-induced contractions.In addition, the effectiveness of test compounds as antagonists or agonists of endothelin's biological tissue response measures the effects of isolated rat thoracic aortic rings on endothelin-induced contractions. (See, for example, Borges et al . (1989) Eur . J. Pharmacol ., 165 : 223-230) or by measuring the ability to contract tissue when added alone.

  Test compounds are prepared as 100 μM stock solutions. If necessary for dissolution, the compound is first dissolved in a small amount of DMSO and then diluted with 150 mM NaCl. Since DMSO can cause relaxation of the aortic ring, control solutions containing various concentrations of DMSO were tested.

The thoracic portion of the adult rat aorta is excised, the endothelium is peeled off by gently rubbing, and it is cut into 3 mm annular sections. Krebs-Henseleit solution saturated with a mixed gas of 95% O ₂ and 5% CO ₂ (118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO ₄ , 1.2 mM KH ₂ PO ₄ , 25 mM NaHCO ₃ , 2.5 mM CaCl _2. Suspend the sections by placing 2 g in a 10 mL organ bath filled with (10 mM D-glucose).

There is a correlation between activity as an antagonist of endothelin-induced thoracic aortic ring contraction and activity as an inhibitor of endothelin binding to endothelin receptors. pA ₂ is a logarithmic linear function of IC ₅₀ .

D. Assay to identify compounds with agonist and / or antagonist activity against ET _B receptors
1. Stimulation of prostacyclin release Since endothelin-1 stimulates the release of prostacyclin from cultured bovine aortic endothelial cells, compounds with agonist or antagonist activity are substantially as described in the report of Filep et al. Endothelin-1 from such endothelial cells obtained by measuring 6-keto PGF _1σ according to the method (Filep et al . (1991) Biochem . Biophys . Res . Commun ., 177 : 171-176). Confirmed by ability to inhibit evoked prostacyclin release. Bovine aortic cells were obtained from collagenase-treated bovine aorta, seeded on culture plates, grown in medium 199 supplemented with heat-inactivated 15% fetal calf serum and L-glutamine (2 mM), penicillin, streptomycin and fungizone. Subculture more than once. Cells are then seeded in the same medium in 6 well plates. When cells reach confluence, the medium is changed and the assay is performed 8 hours later. The cells are then incubated with a) medium alone, b) medium containing endothelin-1 (10 nM), c) test compound alone, d) test compound + endothelin-1 (10 nM).

After a 15 minute incubation, the medium is removed from each well and the concentration of 6-keto PGF _1σ is measured by direct immunoassay. Prostacyclin production is calculated as the difference between the amount of 6-keto PGF _1σ released by cells loaded with endothelin-1 minus the amount released by unloaded cells treated in the same way. Compounds that stimulate 6-keto PGF _1σ release have agonist activity and compounds that inhibit 6-keto PGF _1σ release by endothelin-1 have antagonist activity.

2. Inhibition sarafotoxin 6c of sarafotoxin 6c induced contraction is specific ET _B antagonist that contracts rat fundic sections. The effectiveness of test compounds in inhibiting the sarafotoxin 6c-induced contraction of the rat fundic sections, used as a measure of the ET _B antagonist activity. 10 μM cyclo (D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123; see US Pat. No. 5,114,918 to Ishikawa et al.) Mixed with 95% O ₂ /5% CO ₂ containing 5 μM indomethacin. Two excised rat gastric fundus sections are suspended in a 10 mL organ bath filled with Krebs-Henseleit solution saturated with gas at a load of 1 g. Measure the change in tension on the same axis and record using a polygraph (Grass Polygraph) connected to a force transducer. Sarafotoxin 6c is cumulatively added to one section, and the other section is preincubated with the test compound for 15 minutes before adding the cumulative dose of sarafotoxin 6c. The effect of the test compound on the concentration-response curve for sarafotoxin 6c is examined.

E. Deoxycorticosterone acetate (DOCA) salt hypertensive rat model for evaluating the in vivo activity of selected compounds The activity of selected compounds disclosed in the present invention in deoxycorticosterone acetate (DOCA) salt hypertensive rat models was examined. It was. To perform this test, silastic MDX4-4210 elastomeric implants containing DOCA (47 mg) are prepared according to the method of Ormsby et al . (1973) J. Pharm . Sci ., 62 : 255-257. did. That is, DOCA is incorporated into a silicone rubber embedding and released slowly. To prepare the implant, DOCA is incorporated into unpolymerized silicone rubber, a catalyst is added, and the mixture is cast into a semi-cylindrical shape.

  Sprague-Dawley rats (7-8 weeks old) were subjected to unilateral nephrectomy under ketamine anesthesia, and a DOCA implant was placed on the left dorsal abdomen of the animal. Rats were allowed to recover for 3 weeks. During the recovery period, the animals had free access to 0.9% NaCl drinking solution instead of normal rat chow and drinking water. Rats develop hypertension within 3 weeks.

  All animals were used in the study 21-30 days after surgery. Mean arterial blood pressure in these animals ranged from 165 to 200 mmHg.

  On the day of the experiment, under Brevital anesthesia, a catheter was inserted into the right femoral artery for blood pressure measurement and the right femoral vein for selected compound administration. Animals were placed in restraint cages and allowed to recover for a minimum of 60 minutes or until stable mean arterial blood pressure was recorded. At that time, the selected compound or control vehicle was administered intravenously as an infusion for 60 minutes or by oral gavage. Blood pressure was continuously recorded over an additional 10 hours.

F. Effect of intravenous administration on ET-1-induced pressor response in non-anesthetized rats with autonomic blockade: Model male Sprague-Dawley rats (250-450 g) were anesthetized to assess the in vivo activity of selected compounds (Blebital 50 mg / kg, intraperitoneal administration), a femoral artery for measurement of mean arterial blood pressure (MAP), and a femoral vein for intravenous administration of drugs. Animals were placed in restraint cages to restore consciousness. Thirty minutes later, an autonomic nerve blocker was administered (intravenous administration of methyl atropine nitrate (3 mg / kg) followed by intravenous administration of propranolol (2 mg / kg)). One hour later, the animals received a bolus injection of vehicle (0.5 mL), followed by an intravenous bolus administration of ET-1 (control, 1 μg / kg) 30 minutes later. After recovering from the load, the test compound was administered as an intravenous bolus (0.5 mL), and then ET-1 was loaded again 30 minutes later. Results are expressed as percent inhibition of the ET-1-induced pressor response following test compound administration compared to the pressor response elicited by the control ET-1 load. In some cases, a third ET-1 load was performed 90 minutes after administration of the test compound.

G. result
1. in vitro
For each compound of the Examples was measured _{IC 50} for ET _A receptors and ET _B receptors. Almost all of the compounds for one or both of the ET _A receptors and ET _B receptors, having an _{IC 50} of less than 10 [mu] M. Many compounds have an _{IC 50} of less than about 10 [mu] M, others have an _{IC 50} less than about 1 [mu] M, among them compounds, those having an _{IC 50} of less than about 0.1μM is there. In many compounds, the _{IC 50} for ET _A receptors, considerably lower than for ET _B receptor (10 to 100-fold or more), it is ET _A receptor selective. Others of these compounds are ET _B selective.

2. in vivo
a. N- (4-chloro-3-methyl-5-isoxazolyl) -2- (N- (4-methyl-phenyl) aminocarbonyl) thiophene-3-sulfonamide; N- (4-bromo-3-methyl-5 -Isoxazolyl) -2- [3,4- (methylenedioxy) benzyl] benzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3 4- (methylenedioxy) benzyl) benzo [b] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [β-hydroxy (3,4-methylenedioxy) ) Phenylethyl] thiophene-3-sulfonamide and N- (4-chloro-3-methyl-5-isoxazolyl) -2- (3,4-methylenedioxy-ben For selected compounds, such as ylcarbonyl) thiophene-3-sulfonamide, it was tested in hypertensive rat model, and were effective in lowering blood pressure.

  b. N- (4-chloro-3-methyl-5-isoxazolyl) -2-{[3,4- (methylenedioxy) phenyl] acetyl} thiophene-3-sulfonamide; N- (4-chloro-3-methyl -5-isoxazolyl) -2-{[2-acetyl-4,5- (methylenedioxy) phenyl] aminocarbonyl} thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2-[(4-methoxy-2-methylphenyl) aminocarbonyl] thiophene-3-sulfonamide; N- (4-chloro-3-methyl-5-isoxazolyl) -2- [2-cyano-4,5 -Dimethoxyphenyl) aminocarbonyl] thiophene-3-sulfonamide and N- (4-chloro-3-methyl-5-isoxazolyl) -2- [ When selected compounds such as -methyl-4,5- (methylenedioxy) phenylacetyl] thiophene-3-sulfonamide were tested in a normotensive rat model that blocked autonomic nerves, the dose was as low as 30 mg / kg. Within 30 minutes, the antihypertensive effect was shown to be about 30%, more than 50% at a dose of 60 mg / kg, and was found to have a fairly high activity. An average dose of 30-60 mg / kg of test compound resulted in 40-60% inhibition in pressor response.

  Since changes will be apparent to those skilled in the art, the present invention should be limited only by the scope of the appended claims.

Claims (13)

A method for producing an alkali metal salt of a hydrophobic free sulfonamide, comprising the following steps:
(A) dissolving the free sulfonamide in an organic solvent;
(B) washing the dissolved free sulfonamide with a saturated solution of an alkali metal salt; and (c) recovering the alkali metal salt of the sulfonamide;
Wherein the sulfonamide is of the formula (I)

Wherein Ar ¹ is a 5-membered aromatic heterocycle and Ar ² is selected from the group consisting of thienyl, furyl and pyrrolyl.
Having a method. The method of claim 1, wherein Ar ¹ is selected from the group consisting of isoxazolyl and thiazolyl. A pharmaceutically acceptable salt prepared by the method of claim 1 or 2, wherein Ar ² is of formula IV:

Where X is S; and
R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the following (i) or (ii):
(I) R ⁸ , R ⁹ and R ¹⁰ each have hydrogen or up to about 50 carbon atoms, each independently hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, Heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C (O) R ¹⁸ , acetoxy- (CH═CH) —, CO ₂ R ¹⁸ , SH, (CH ₂ ) _r C ( O) (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH) _s (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r C (O) (CH═CH) _s (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r (CH═CH) _s C (O) (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r NH (CH═CH) _s (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _{r (CH = CH) s NH} (CH 2) n R 18, (CH 2) r C (O) NH (CH 2) n R 18, C (O) (CH 2) r NH (CH 2) n R ¹⁸ , (CH ₂ ) _r NH (CH ₂ ) _n R ¹⁸ , (CH ₂ ) _r R ¹⁸ , S (O) _m R ¹⁸ (m is 0 to 2, s, n and r are each independently 0 -6), HNOH, NR ¹⁸ R ¹⁹ , NO ₂ , N ₃ , OR ¹⁸ , R ¹⁹ NCOR ¹⁸ and CONR ¹⁹ R ¹⁸ , wherein R ¹⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkyl aryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C ^{(O) R 20} and ^{_{S (O) n R 20 (}} n is 0-2 der ) Is selected from; R ¹⁸ and R ²⁰ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocyclic, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl Any of the groups described for R ⁸ , R ⁹ and R ¹⁰ are unsubstituted or substituted with the substituents described for Z, wherein Z is hydrogen, halide, pseudohalide, alkyl, Alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C (O) R ²¹ , CO ₂ R ²¹ , SH, S (O) _n R ²¹ (n is 0 to 2), NH _{^{H, NR 22 R 21, NO}} 2, N 3, OR 21, be R 22 NCOR ²¹ and ^{CONR 22 R 21; R} 22 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, Selected from alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C (O) R ²³ and S (O) _n R ²³ (where n is 0 to 2); and R ²¹ and R ²³ are independently Selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; or
(Ii) any two of R ⁸ , R ⁹ and R ¹⁰ together with the carbon to which they are attached form an about 3 to about 16 member aromatic ring, the ring comprising one or more substituents Each substituent is independently selected from Z; the others of R ⁸ , R ⁹ and R ¹⁰ are selected as in (i).   The process according to claim 1, wherein the organic solvent is ethyl acetate.   The process according to claim 1, wherein the alkali metal is sodium, potassium, calcium or magnesium.   6. A process according to claim 5, wherein the alkali metal is sodium.   7. A process according to claim 6, wherein the saturated solution of alkali metal salt is saturated sodium bicarbonate or sodium carbonate.   8. The method of claim 7, wherein the saturated solution of alkali metal salt is saturated sodium bicarbonate.   The step of recovering the product of step (b); concentrating the product; crystallizing the product in one or more water-immiscible organic solvents; and filtering the sulfonamide salt The method of claim 1, comprising the step of recovering.   The process according to claim 9, wherein the water-immiscible organic solvent is dichloromethane and ether.   The method of claim 9, further comprising purifying the sulfonamide salt after recovery. The free sulfonamide is 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole; N ² - (3- cyanomethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolyl Rusuru sulfamoyl) ^{-2-thiophenecarboxamide;} N 2 - (3- acetyloxymethyl-2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolyl Rusuru sulfamoyl) -2-thiophenecarboxamide; or ^N 2 - (3- hydroxymethyl - 2,4,6-trimethylphenyl) -3- (4-chloro-3-methyl-5-isoxazolylsulfamoyl) -2-thiophenecarboxa A de The method of claim 1. The free sulfonamidic acid is 4-chloro-3-methyl-5- (2- (2- (6-methylbenzo [d] [1,3] dioxol-5-yl) acetyl) -3-thienylsulfonamido) isoxazole This material is (a) 5-chloromethyl-6-methylbenzo [d] [1,3] dioxole and activated magnesium mixed in tetrahydrofuran to form a Grignard reagent; (b) reaction mixture the mixture from step (c) (b) where; the ^{N 2} - methyl-3- (4-chloro-3-methyl-5-isoxazolyl Rusuru sulfamoyl) -2-thiophenecarboxamide added bromide - methoxy -N ² By successively diluting with concentrated inorganic acid and organic solvent to form an aqueous layer and an organic layer; and (d) drying the organic layer to obtain a residue containing free acid. The method according to claim 1, wherein the method is manufactured.